22 February 2011
Israeli scientists have developed compounds that could be better treatments for genetic diseases than current drugs.
Timor Baasov and his colleagues at the Israel Institute of Technology have improved compounds used to suppress faults in genes called nonsense mutations.
Nonsense mutations, which cause more than 1800 human diseases, are alterations in the genetic code that stop protein production prematurely, leading to truncated or nonfunctional proteins. Gene therapy is one treatment, but it's had limited success. With suppression therapy, small molecules allow cells' protein producing equipment to skip over nonsense mutations to restore the proteins. Aminoglycosides - antibiotic amine-modified sugars - are the only clinically available drug family known to be effective in suppression therapy, but at effective doses, the compounds have high human toxicity.
To reduce the toxicity, the team introduced a methyl group onto two aminoglycosides. They tested the new derivatives in an in vitro suppression test on six different nonsense mutations for different diseases and carried out toxicity tests on human cells. They found that the compounds exhibited significantly improved activity and reduced toxicity compared to gentamicin, an aminoglycoside antibiotic used to treat bacterial infections.
'Treating genetic disorders is one of the biggest challenges of modern medicine. The likelihood that suppression therapy could be used clinically is very feasible,' says Baasov.
'The data emphasise the enormous potential of modified aminoglycosides for [nonsense suppression] therapy to combat nonsense mutation-based disorders with limited or no current therapeutic options,' says Uwe Wolfrum, a cell biologist at the Johannes Gutenberg University of Mainz, Germany. 'This raises hope for future clinical trials.'
'Our lead compounds are under intensive examination on numerous genetic disease models including cystic fibrosis, Hurler syndrome, Rett syndrome and Usher syndrome,' concludes Baasov.
Amaya Camara-Campos
Source: RSC
Note: To read original post click on the title of the post.
Thursday, February 24, 2011
Friday, February 18, 2011
Licence rules hinder work on rare disease
Animal model off-limits to Rett-syndrome researchers.
Stashed away somewhere in a freezer in Cambridge, Massachusetts, is a mouse embryo that Etienne Joly would dearly like to get his hands on.
Joly is an immunologist based in Toulouse, France, with a keen interest in Rett syndrome, an incurable and debilitating disease that almost exclusively affects young girls. The mouse, developed by a team at the Novartis Institutes for Biomedical Research in Cambridge, carries a fluorescently tagged version of the gene that is mutated in the disease. It is the perfect tool, Joly says, for testing an idea he has about Rett syndrome. But a thicket of legal restrictions puts the mouse off-limits to anyone outside Novartis, even though scientists at the company are no longer using the model in their work on Rett syndrome.
"All scientists and families are asking for is the right to look into this disease and to try to understand it better," says Joly, who has embarked on a letter-writing campaign against the restrictions. "And when you know that there is a tool, but you can't use it because some lawyer says that you can't have the materials, then you get angry." Scientists and experts in intellectual-property issues say that the case shows how science can be impeded when onerous licensing rules govern the sharing of research materials.
Girls with Rett syndrome are healthy as babies, then progressively lose the ability to speak, move, eat and breathe normally. Because the disease is rare, affecting just one in 10,000 to 20,000 girls, it is an unattractive target for drug companies. Academic researchers have picked up the slack, and the field has moved at breakneck speed in recent years, from the 1999 discovery that defects in the gene MECP2 cause the disease, to clinical trials of possible treatments today.
Yet no one knows how the mutation causes the disease. A few years ago, Joly, who works at the Institute of Pharmacology and Structural Biology, came up with what he calls a "slightly unconventional" idea that the Rett-syndrome gene might have a role in regulating immune responses in the central nervous system. To explore his hypothesis, Joly needed an animal model that would allow him to trace where the gene is expressed.
In 2008, Joly learned about the engineered mouse. Led by molecular biologist Cecile Blaustein, the Novartis team had joined a copy of the mouse Mecp2 gene to a copy of the gene that makes enhanced green fluorescent protein (EGFP) to produce an animal in which the gene's activity can be traced throughout the brain and body (R. S. Schmid et al. Neuroreport 19, 393–398; 2008).
But after three years of trying, neither Joly nor any other Rett-syndrome researcher has been able to gain access to the mouse. When researchers asked to share it, Blaustein and her colleagues said that they would have liked to but couldn't because of the terms of Novartis's licence on EGFP, which it obtained from GE Healthcare.
Novartis and GE have been unable to negotiate a way to share the mice, says Jeff Lockwood, spokesman for the Novartis Institutes for Biomedical Research — even though Novartis has ended its research project on the mice.
When Monica Coenraads, executive director of the Rett Syndrome Research Trust in Trumbull, Connecticut, tried to broker an agreement to share the mice, GE and Novartis asked the US National Institutes of Health (NIH) in Bethesda, Maryland, to distribute the mice through its Mutant Mouse Regional Resource Centers. But Lili Portilla, senior adviser for technology transfer at the NIH National Center for Research Resources, which funds the resource centre, says that GE placed such burdensome terms on the sharing that the NIH eventually gave up. For instance, researchers would not have been allowed to share the results of their research with the NIH, says Portilla.
GE spokesman Conor McKechnie blames the "third parties" from which GE gained the rights to the EGFP protein for the onerous licensing requirements. But David Einhorn, house counsel at the Jackson Laboratory in Bar Harbor, Maine, which distributes mice to researchers around the world, questions GE's contention. He points out that many other mouse models that incorporate the gene for EGFP have been made and shared without objection from GE or from the institutions that originally discovered and licensed the EGFP patents.
Researchers have had trouble sharing resources for decades, but the situation seems to be getting worse. A 2007 study, for instance, found that 18% of academics' requests for research materials from other academic labs were not fulfilled (see 'Limited access') — almost twice as many as found in a survey taken during the 1990s. For materials requested from industry, the 2007 study found, one-third of academics' requests were declined (J. P. Walsh, W. M. Cohen and C. Cho Res. Pol. 36, 1184–1203; 2007).
Companies that don't want to share their resources don't usually publish papers describing them, says lawyer Tania Bubela of the University of Alberta School of Public Health in Edmonton, Canada. A publication changes the picture, she says. "The obligation of publication is to make your data and reagents available, so that people can replicate the results."
With no sign of a resolution, other labs have resorted to remaking the mouse model. Adrian Bird, director of the University of Edinburgh's Wellcome Trust Centre for Cell Biology, UK, says that his lab has re-engineered the mice and will distribute them through a repository, such as the Jackson Laboratory, as soon as his colony is large enough.
Bird and others say that it is unfortunate that scientists have had to delay research on the syndrome and spend money to regenerate a model that could already be in use.
"If you were to ask the families of people affected by this disease, they would say that every minute counts," says Bird.
Source: Nature News
Note: To see the original page click on the title of the post
Stashed away somewhere in a freezer in Cambridge, Massachusetts, is a mouse embryo that Etienne Joly would dearly like to get his hands on.
Joly is an immunologist based in Toulouse, France, with a keen interest in Rett syndrome, an incurable and debilitating disease that almost exclusively affects young girls. The mouse, developed by a team at the Novartis Institutes for Biomedical Research in Cambridge, carries a fluorescently tagged version of the gene that is mutated in the disease. It is the perfect tool, Joly says, for testing an idea he has about Rett syndrome. But a thicket of legal restrictions puts the mouse off-limits to anyone outside Novartis, even though scientists at the company are no longer using the model in their work on Rett syndrome.
"All scientists and families are asking for is the right to look into this disease and to try to understand it better," says Joly, who has embarked on a letter-writing campaign against the restrictions. "And when you know that there is a tool, but you can't use it because some lawyer says that you can't have the materials, then you get angry." Scientists and experts in intellectual-property issues say that the case shows how science can be impeded when onerous licensing rules govern the sharing of research materials.
Girls with Rett syndrome are healthy as babies, then progressively lose the ability to speak, move, eat and breathe normally. Because the disease is rare, affecting just one in 10,000 to 20,000 girls, it is an unattractive target for drug companies. Academic researchers have picked up the slack, and the field has moved at breakneck speed in recent years, from the 1999 discovery that defects in the gene MECP2 cause the disease, to clinical trials of possible treatments today.
Yet no one knows how the mutation causes the disease. A few years ago, Joly, who works at the Institute of Pharmacology and Structural Biology, came up with what he calls a "slightly unconventional" idea that the Rett-syndrome gene might have a role in regulating immune responses in the central nervous system. To explore his hypothesis, Joly needed an animal model that would allow him to trace where the gene is expressed.
In 2008, Joly learned about the engineered mouse. Led by molecular biologist Cecile Blaustein, the Novartis team had joined a copy of the mouse Mecp2 gene to a copy of the gene that makes enhanced green fluorescent protein (EGFP) to produce an animal in which the gene's activity can be traced throughout the brain and body (R. S. Schmid et al. Neuroreport 19, 393–398; 2008).
But after three years of trying, neither Joly nor any other Rett-syndrome researcher has been able to gain access to the mouse. When researchers asked to share it, Blaustein and her colleagues said that they would have liked to but couldn't because of the terms of Novartis's licence on EGFP, which it obtained from GE Healthcare.
Novartis and GE have been unable to negotiate a way to share the mice, says Jeff Lockwood, spokesman for the Novartis Institutes for Biomedical Research — even though Novartis has ended its research project on the mice.
When Monica Coenraads, executive director of the Rett Syndrome Research Trust in Trumbull, Connecticut, tried to broker an agreement to share the mice, GE and Novartis asked the US National Institutes of Health (NIH) in Bethesda, Maryland, to distribute the mice through its Mutant Mouse Regional Resource Centers. But Lili Portilla, senior adviser for technology transfer at the NIH National Center for Research Resources, which funds the resource centre, says that GE placed such burdensome terms on the sharing that the NIH eventually gave up. For instance, researchers would not have been allowed to share the results of their research with the NIH, says Portilla.
GE spokesman Conor McKechnie blames the "third parties" from which GE gained the rights to the EGFP protein for the onerous licensing requirements. But David Einhorn, house counsel at the Jackson Laboratory in Bar Harbor, Maine, which distributes mice to researchers around the world, questions GE's contention. He points out that many other mouse models that incorporate the gene for EGFP have been made and shared without objection from GE or from the institutions that originally discovered and licensed the EGFP patents.
Researchers have had trouble sharing resources for decades, but the situation seems to be getting worse. A 2007 study, for instance, found that 18% of academics' requests for research materials from other academic labs were not fulfilled (see 'Limited access') — almost twice as many as found in a survey taken during the 1990s. For materials requested from industry, the 2007 study found, one-third of academics' requests were declined (J. P. Walsh, W. M. Cohen and C. Cho Res. Pol. 36, 1184–1203; 2007).
Companies that don't want to share their resources don't usually publish papers describing them, says lawyer Tania Bubela of the University of Alberta School of Public Health in Edmonton, Canada. A publication changes the picture, she says. "The obligation of publication is to make your data and reagents available, so that people can replicate the results."
With no sign of a resolution, other labs have resorted to remaking the mouse model. Adrian Bird, director of the University of Edinburgh's Wellcome Trust Centre for Cell Biology, UK, says that his lab has re-engineered the mice and will distribute them through a repository, such as the Jackson Laboratory, as soon as his colony is large enough.
Bird and others say that it is unfortunate that scientists have had to delay research on the syndrome and spend money to regenerate a model that could already be in use.
"If you were to ask the families of people affected by this disease, they would say that every minute counts," says Bird.
Source: Nature News
Note: To see the original page click on the title of the post
Saturday, January 8, 2011
Study shows promise for new drug to treat Fragile X
Rush University Medical Center participating in follow-up study
The first drug to treat the underlying disorder instead of the symptoms of Fragile X, the most common cause of inherited intellectual disability, shows some promise according to a new study published in the January 5 issue of Science Translational Medicine. Researchers from Rush University Medical Center helped design the study and are now participating in the larger follow-up clinical trial.
The data from the early trial of 30 Fragile X patients, found the drug, called AFQ056, made by Novartis Pharmaceuticals, helped improve symptoms in some patients. Patients who had the best response have a kind of "fingerprint" in their DNA that could act as a marker to determine who should get treatment.
"This is an exciting development. It is the first time we have a treatment targeted to the underlying disorder, as opposed to supportive treatment of the behavioral symptoms, in a developmental brain disorder causing intellectual disability. This drug could be a model for treatment of other disorders such as autism," said pediatric neurologist Dr. Elizabeth Berry-Kravis, a study author and director of the Fragile X Clinic and Research Program and the Fragile X-Associated Disorders Program at Rush.
The drug is designed to block the activity of mGluR5, a receptor protein on brain cells that is involved in most aspects of normal brain function, including regulation of the strength of brain connections, a key process required for learning and memory. Fragile X patients have a mutation in a single gene, known as Fragile X Mental Retardation-1 or FMR1. The mutation prevents FMR1 from making its protein, called FMRP, such that FMRP is missing in the brain. FMRP normally acts as a blocker or "brake" for brain cell pathways activated by mGluR5. When FMRP is missing, mGluR5 pathways are overactive resulting in abnormal connections in the brain and the behavioral and cognitive impairments associated with Fragile X.
The research team, led by Sebastien Jacquemont of Vaudois University in Switzerland in collaboration with Baltazar Gomez-Mancilla of Novartis, found no significant effects of treatment when the entire group of 30 patients was analyzed. However, in a subsequent analysis, seven patients who had a fully methylated gene, a gene that was fully shut down, presumably resulting in no FMR protein in the blood or brain, showed significant improvement in behavior, hyperactivity and inappropriate speech with the treatment compared to placebo.
"The treatment period in this pilot study was very short and longer treatment might have been needed to see improvement in the whole group of patients. Importantly, the drug was well-tolerated and there were no safety problems," said Berry-Kravis.
A larger study of the drug is now underway that will recruit 160 patients worldwide and test the effects of a longer period of treatment. Rush University Medical Center is one of the participating sites.
Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups. It is the most common known single gene cause of autism or "autistic-like" behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development. The impairment can range from learning disabilities to more severe cognitive and intellectual disabilities.
###
The Fragile X Clinic at Rush was started in 1992 to serve the unique needs of the Fragile X population. The clinic and research center is dedicated to helping people with Fragile X syndrome and their families, as well as furthering understanding of the syndrome, and developing new treatments targeted to the neural basis of the disorder. Dr. Elizabeth Berry-Kravis has been involved in research and clinical work with individuals with Fragile X syndrome for 14 years, and has been honored with the National Fragile X Foundation Jarrett Cole Clinical Award.
Rush is a not-for-profit health care, education and research enterprise comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health. Rush University is home to one of the first medical colleges in the Midwest and one of the nation's top-ranked nursing colleges, as well as graduate programs in allied health, health systems management and biomedical research.
Contact: Kim Waterman
Kimberly_Waterman@rush.edu
312-942-7820
Rush University Medical Center
Public release date: 7-Jan-2011
Source: EurekaAlert
The first drug to treat the underlying disorder instead of the symptoms of Fragile X, the most common cause of inherited intellectual disability, shows some promise according to a new study published in the January 5 issue of Science Translational Medicine. Researchers from Rush University Medical Center helped design the study and are now participating in the larger follow-up clinical trial.
The data from the early trial of 30 Fragile X patients, found the drug, called AFQ056, made by Novartis Pharmaceuticals, helped improve symptoms in some patients. Patients who had the best response have a kind of "fingerprint" in their DNA that could act as a marker to determine who should get treatment.
"This is an exciting development. It is the first time we have a treatment targeted to the underlying disorder, as opposed to supportive treatment of the behavioral symptoms, in a developmental brain disorder causing intellectual disability. This drug could be a model for treatment of other disorders such as autism," said pediatric neurologist Dr. Elizabeth Berry-Kravis, a study author and director of the Fragile X Clinic and Research Program and the Fragile X-Associated Disorders Program at Rush.
The drug is designed to block the activity of mGluR5, a receptor protein on brain cells that is involved in most aspects of normal brain function, including regulation of the strength of brain connections, a key process required for learning and memory. Fragile X patients have a mutation in a single gene, known as Fragile X Mental Retardation-1 or FMR1. The mutation prevents FMR1 from making its protein, called FMRP, such that FMRP is missing in the brain. FMRP normally acts as a blocker or "brake" for brain cell pathways activated by mGluR5. When FMRP is missing, mGluR5 pathways are overactive resulting in abnormal connections in the brain and the behavioral and cognitive impairments associated with Fragile X.
The research team, led by Sebastien Jacquemont of Vaudois University in Switzerland in collaboration with Baltazar Gomez-Mancilla of Novartis, found no significant effects of treatment when the entire group of 30 patients was analyzed. However, in a subsequent analysis, seven patients who had a fully methylated gene, a gene that was fully shut down, presumably resulting in no FMR protein in the blood or brain, showed significant improvement in behavior, hyperactivity and inappropriate speech with the treatment compared to placebo.
"The treatment period in this pilot study was very short and longer treatment might have been needed to see improvement in the whole group of patients. Importantly, the drug was well-tolerated and there were no safety problems," said Berry-Kravis.
A larger study of the drug is now underway that will recruit 160 patients worldwide and test the effects of a longer period of treatment. Rush University Medical Center is one of the participating sites.
Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups. It is the most common known single gene cause of autism or "autistic-like" behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development. The impairment can range from learning disabilities to more severe cognitive and intellectual disabilities.
###
The Fragile X Clinic at Rush was started in 1992 to serve the unique needs of the Fragile X population. The clinic and research center is dedicated to helping people with Fragile X syndrome and their families, as well as furthering understanding of the syndrome, and developing new treatments targeted to the neural basis of the disorder. Dr. Elizabeth Berry-Kravis has been involved in research and clinical work with individuals with Fragile X syndrome for 14 years, and has been honored with the National Fragile X Foundation Jarrett Cole Clinical Award.
Rush is a not-for-profit health care, education and research enterprise comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health. Rush University is home to one of the first medical colleges in the Midwest and one of the nation's top-ranked nursing colleges, as well as graduate programs in allied health, health systems management and biomedical research.
Contact: Kim Waterman
Kimberly_Waterman@rush.edu
312-942-7820
Rush University Medical Center
Public release date: 7-Jan-2011
Source: EurekaAlert
Monday, December 6, 2010
New Clinical Trial: Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)
Purpose
The investigators are recruiting children for a research study using a medication known as IGF-1 (mecasermin or INCRELEX) to see if it improves the health of children with Rett syndrome (RTT). To participate in the study your child must be female, between the ages of 2 to 12 and have a genetic diagnosis (MECP2 deletion or mutation) of Rett Syndrome. As you may know, there is no treatment for this illness. Currently, the standard management of Rett syndrome is supportive, which means attempting to prevent complications and treatment of symptoms.
This study involves testing an investigational drug, which means that even though IGF-1 is approved by the Food and Drug Administration (FDA) for use in children, it has not been used before to treat Rett syndrome specifically. Information from this research will help determine whether the drug should be approved by the FDA in the future for the treatment of Rett Syndrome.
There are three goals to this study:
1. As one of the features of Rett Syndrome is unstable vital signs, the investigators are trying to determine if IGF-1 has any effect on normalizing your child's pulse, blood pressure and breathing pattern. During PHASE 2, a device called BioRadio® will be used to monitor vital signs in a non-invasive way. This information will be recorded and stored on the accompanying laptop. Before starting PHASE 2, the investigators would like to "beta-test" the BioRadio® in PHASE 1. As such, the investigators may ask you to try using the BioRadio® with your child to test the fit and the performance of the equipment. Should you choose to enroll your child in PHASE 2, the investigators will then ask that your child wear the BioRadio® for two hours, on two consecutive days every four weeks.
2. The safety of IGF-1 in children with Rett syndrome. The study personnel will ask you to complete a medication diary and side effect reporting form on a regular basis. They will assist you in completing this by telephone interviews. Your child will undergo 2 lumbar punctures performed at the bedside in the clinical research facility. In addition, laboratory tests will be performed throughout the study to evaluate the safety of IGF-1. These will be blood tests similar to those provided in routine clinical care. Your child will undergo regular non-invasive comprehensive physical examinations including neurological and eye examination, tonsil evaluation, electrocardiograms (ECG), measurement of height, weight and head circumference.
3. IGF-1 may improve your child's behavior, communication and speech. In order to measure this, the investigators will evaluate your child once during each month of treatment with neurodevelopmental assessments and a neurological exam. All of the tests used during these evaluations are non-invasive. the investigators will also ask you what your impressions are about her behavior and day-to-day activities through a structured parental interview and various questionnaires.
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To read more about this, please click on the title
Source: Clinicaltrials.gov
The investigators are recruiting children for a research study using a medication known as IGF-1 (mecasermin or INCRELEX) to see if it improves the health of children with Rett syndrome (RTT). To participate in the study your child must be female, between the ages of 2 to 12 and have a genetic diagnosis (MECP2 deletion or mutation) of Rett Syndrome. As you may know, there is no treatment for this illness. Currently, the standard management of Rett syndrome is supportive, which means attempting to prevent complications and treatment of symptoms.
This study involves testing an investigational drug, which means that even though IGF-1 is approved by the Food and Drug Administration (FDA) for use in children, it has not been used before to treat Rett syndrome specifically. Information from this research will help determine whether the drug should be approved by the FDA in the future for the treatment of Rett Syndrome.
There are three goals to this study:
1. As one of the features of Rett Syndrome is unstable vital signs, the investigators are trying to determine if IGF-1 has any effect on normalizing your child's pulse, blood pressure and breathing pattern. During PHASE 2, a device called BioRadio® will be used to monitor vital signs in a non-invasive way. This information will be recorded and stored on the accompanying laptop. Before starting PHASE 2, the investigators would like to "beta-test" the BioRadio® in PHASE 1. As such, the investigators may ask you to try using the BioRadio® with your child to test the fit and the performance of the equipment. Should you choose to enroll your child in PHASE 2, the investigators will then ask that your child wear the BioRadio® for two hours, on two consecutive days every four weeks.
2. The safety of IGF-1 in children with Rett syndrome. The study personnel will ask you to complete a medication diary and side effect reporting form on a regular basis. They will assist you in completing this by telephone interviews. Your child will undergo 2 lumbar punctures performed at the bedside in the clinical research facility. In addition, laboratory tests will be performed throughout the study to evaluate the safety of IGF-1. These will be blood tests similar to those provided in routine clinical care. Your child will undergo regular non-invasive comprehensive physical examinations including neurological and eye examination, tonsil evaluation, electrocardiograms (ECG), measurement of height, weight and head circumference.
3. IGF-1 may improve your child's behavior, communication and speech. In order to measure this, the investigators will evaluate your child once during each month of treatment with neurodevelopmental assessments and a neurological exam. All of the tests used during these evaluations are non-invasive. the investigators will also ask you what your impressions are about her behavior and day-to-day activities through a structured parental interview and various questionnaires.
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To read more about this, please click on the title
Source: Clinicaltrials.gov
Saturday, December 4, 2010
Rett Syndrome Documentary on CNN-IBN
Rett syndrome story (Indian Rett syndrome foundation)
Please watch CNN-IBN Channel today (4th December) at 9.30 PM and tomorrow (5th December) at 5.30PM and 10.30PM
Share this information with other too.
Please watch CNN-IBN Channel today (4th December) at 9.30 PM and tomorrow (5th December) at 5.30PM and 10.30PM
Share this information with other too.
Tuesday, November 30, 2010
Tuesday, November 16, 2010
New Data Uncover Common Molecular Pathways Between Rett Syndrome, Autism and Schizophrenia
The laboratory of Huda Zoghbi, where the discovery that mutations in the gene MECP2 cause the severe childhood neurological disorder Rett Syndrome was made, has taken yet another step toward unraveling the complex epigenetic functions of this gene, implicated also in cases of autism, bipolar disease and childhood onset schizophrenia. The November 11 issue of Nature reports that removing MECP2 from a small group of neurons that typically make the inhibitory neurotransmitter, GABA, recapitulates many symptoms of Rett as well as numerous neuropsychiatric disorders.
The identification of the genetic basis of Rett allowed the development of a number of mouse models of the disorder, accurately reproducing the range of symptoms seen in humans. These are considered to be among the best existing models of neurological disease.
While removing MECP2 from every cell results in full-blown Rett symptoms, the Zoghbi lab during the past few years has been using genetic tools to knock out the gene from distinct subsets of specialized brain cells called neurons, in an attempt to correlate certain neuronal populations with specific symptoms.
GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the brain. Neurons releasing GABA regulate the nervous system by acting like traffic lights on the brain’s information highway. Zoghbi and Hsiao-Tuan Chao, a postdoctoral fellow in the lab and lead author of the study, use this analogy to describe the action of GABA in allowing for a balanced level of neuronal activity by controlling the strength and timing of information transfer. Surprisingly, Zoghbi, Chao and colleagues found that removing MeCP2 from the small number of GABA-producing neurons reduced production of the neurotransmitter by about 30%. This reduction reproduced many symptoms of Rett including the paw-clasping that mimics the classical hand-wringing stereotypies. After a brief period of apparently normal development, the mice display brain hyperexcitability, impaired respiration, and loss of muscle control and strength and premature lethality. Learning, memory and sensory responses are also altered. Interestingly, the mice engaged in repetitive movements reminiscent of compulsive behavior seen in a number of neuropsychiatric disorders.
The study raises a number of important points. It implicates GABA as a key player in Rett and suggests that boosting the activity of GABA -producing neurons may help to alleviate the severity of some symptoms. It also begs the question: If a 30% reduction in GABA causes Rett symptoms, could a more subtle perturbation of 10% or 20% lead to certain neuropsychiatric disorders? This study suggests a possible pathway which can now be explored to answer the question fully.
“This study revealed to us the critical role of MECP2 in modulating the levels of GABA in inhibitory neurons and pinpointed all the neuropsychiatric symptoms that develop when the function of inhibitory neurons is compromised. Identifying the cellular and chemical basis of such symptoms is a first step in efforts aimed at understanding and, one day, treating such disorders,” said Zoghbi.
Dr. Zoghbi, who was first drawn into Rett research through her clinical experience at Baylor College of Medicine, is a Howard Hughes investigator and a Rett Syndrome Research Trust Scientific Advisor.
Monica Coenraads, Executive Director at the Rett Syndrome Research Trust which helped to fund this work, says “The field of Rett research has benefited incalculably from Huda Zoghbi’s dedication and perseverance. Her latest results suggest that GABAergic pathways are ripe for exploration not only as therapeutic intervention for Rett Syndrome but also for a much wider class of neurological disease.”
About Rett Syndrome
Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Although some victims of Rett Syndrome do not survive childhood, most live to become adults who require total, round-the-clock care.
About Rett Syndrome Research Trust
The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. The goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high level research. RSRT is in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects. www.reverserett.org
About Baylor College of Medicine
Baylor College of Medicine in Houston is recognized as a premier academic health science center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked as one of the top 25 medical schools for research in U.S. News & World Report. BCM is listed 13th among all U.S. medical schools for National Institutes of Health funding, and No. 2 in the nation in federal funding for research and development in the biological sciences at universities and colleges by the National Science Foundation. Located in the Texas Medical Center, BCM has affiliations with eight teaching hospitals, each known for medical excellence. Currently, BCM trains more than 3,000 medical, graduate, nurse anesthesia, and physician assistant students, as well as residents and post-doctoral fellows. BCM is also home to the Baylor Clinic, an adult clinical practice that includes advanced technologies for faster, more accurate diagnosis and treatment, access to the latest clinical trials and discoveries, and groundbreaking healthcare based on proven research.
Source: Rett Syndrome Research Trust
Contact Person:
Monica Coenraads
Executive Director, RSRT
monica@rsrt.org
203.445.0041
The identification of the genetic basis of Rett allowed the development of a number of mouse models of the disorder, accurately reproducing the range of symptoms seen in humans. These are considered to be among the best existing models of neurological disease.
While removing MECP2 from every cell results in full-blown Rett symptoms, the Zoghbi lab during the past few years has been using genetic tools to knock out the gene from distinct subsets of specialized brain cells called neurons, in an attempt to correlate certain neuronal populations with specific symptoms.
GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the brain. Neurons releasing GABA regulate the nervous system by acting like traffic lights on the brain’s information highway. Zoghbi and Hsiao-Tuan Chao, a postdoctoral fellow in the lab and lead author of the study, use this analogy to describe the action of GABA in allowing for a balanced level of neuronal activity by controlling the strength and timing of information transfer. Surprisingly, Zoghbi, Chao and colleagues found that removing MeCP2 from the small number of GABA-producing neurons reduced production of the neurotransmitter by about 30%. This reduction reproduced many symptoms of Rett including the paw-clasping that mimics the classical hand-wringing stereotypies. After a brief period of apparently normal development, the mice display brain hyperexcitability, impaired respiration, and loss of muscle control and strength and premature lethality. Learning, memory and sensory responses are also altered. Interestingly, the mice engaged in repetitive movements reminiscent of compulsive behavior seen in a number of neuropsychiatric disorders.
The study raises a number of important points. It implicates GABA as a key player in Rett and suggests that boosting the activity of GABA -producing neurons may help to alleviate the severity of some symptoms. It also begs the question: If a 30% reduction in GABA causes Rett symptoms, could a more subtle perturbation of 10% or 20% lead to certain neuropsychiatric disorders? This study suggests a possible pathway which can now be explored to answer the question fully.
“This study revealed to us the critical role of MECP2 in modulating the levels of GABA in inhibitory neurons and pinpointed all the neuropsychiatric symptoms that develop when the function of inhibitory neurons is compromised. Identifying the cellular and chemical basis of such symptoms is a first step in efforts aimed at understanding and, one day, treating such disorders,” said Zoghbi.
Dr. Zoghbi, who was first drawn into Rett research through her clinical experience at Baylor College of Medicine, is a Howard Hughes investigator and a Rett Syndrome Research Trust Scientific Advisor.
Monica Coenraads, Executive Director at the Rett Syndrome Research Trust which helped to fund this work, says “The field of Rett research has benefited incalculably from Huda Zoghbi’s dedication and perseverance. Her latest results suggest that GABAergic pathways are ripe for exploration not only as therapeutic intervention for Rett Syndrome but also for a much wider class of neurological disease.”
About Rett Syndrome
Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Although some victims of Rett Syndrome do not survive childhood, most live to become adults who require total, round-the-clock care.
About Rett Syndrome Research Trust
The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. The goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high level research. RSRT is in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects. www.reverserett.org
About Baylor College of Medicine
Baylor College of Medicine in Houston is recognized as a premier academic health science center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked as one of the top 25 medical schools for research in U.S. News & World Report. BCM is listed 13th among all U.S. medical schools for National Institutes of Health funding, and No. 2 in the nation in federal funding for research and development in the biological sciences at universities and colleges by the National Science Foundation. Located in the Texas Medical Center, BCM has affiliations with eight teaching hospitals, each known for medical excellence. Currently, BCM trains more than 3,000 medical, graduate, nurse anesthesia, and physician assistant students, as well as residents and post-doctoral fellows. BCM is also home to the Baylor Clinic, an adult clinical practice that includes advanced technologies for faster, more accurate diagnosis and treatment, access to the latest clinical trials and discoveries, and groundbreaking healthcare based on proven research.
Source: Rett Syndrome Research Trust
Contact Person:
Monica Coenraads
Executive Director, RSRT
monica@rsrt.org
203.445.0041
PTC Therapeutics: Development of treatment for Genetic Disorder
PTC applies its expertise in RNA biology and drug development to pioneer novel oral treatments for patients living with serious and life-threatening conditions.
Ataluren for Genetic Disorders
Ataluren (PTC124®) is an investigational drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation.
A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA) .
Click here to read Frequently Asked Questions about ataluren.
Translation of an mRNA into protein
Mechanism of Action
In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results.
Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional (eg, the CFTR protein in nmCF. the Factor VIII/Factor IX protein in nmHA/B or the dystrophin protein in nmDBMD ).
Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal.
Ataluren, taken orally, has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body.
Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimated that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. Besides nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD), nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA), these genetic disorders include a range of serious diseases across multiple therapeutic areas including, spinal muscular atrophy, lysosomal storage disorders, and some forms of cancer.
PTC124 Targets Genetic Disorders Caused by Nonsense Mutations
(Click the link above to read the article)
Genetic Testing
Ataluren has the potential to treat any genetic disorder caused by a nonsense mutation. Although current clinical trials involve only nonsense mutation CF and nonsense mutation HA/B, future trials are anticipated in other genetic disorders caused by a nonsense mutation. To determine whether a genetic disorder is caused by a nonsense mutation, patients require genetic testing. Genetic testing is done by a simple blood test that is ordered by a physician working in concert with a genetic lab.
Laboratories performing genetic testing vary by disorder and location. The NIH-funded website, www.genetest.org provides a listing of laboratories and contact information.
Ongoing Clinical Trials
* nmCF: PTC has initiated a longer-term, Phase 3 clinical study of ataluren in patients with nonsense mutation CF. The main goals of this study are to understand whether ataluren can improve how nmCF patients feel and function and whether the drug can safely be given over a long period. The trial is a multi-center, randomized, double-blind, placebo-controlled study.
* nmHA/B: PTC has initiated a Phase 2a clinical trial of ataluren in patients with nonsense mutation hemophilia type A and B (nmHA and nmHB). The trial is a multi-center, open label, dose escalation study. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation.
* nmMMA: PTC has initiated a Phase 2 clinical trial of ataluren in patients with nonsense mutation methylmalonic acidemia (nmMMA). The trial is a non-randomized, open-label trial. Its main goals are to understand whether ataluren can be tolerated and can decrease MMacid levels.
Completed Clinical Trials
*
Phase 2b Data nonsense mutation DBMD (nmDBMD): Final analyses of Phase 2b efficacy data suggest the investigational new drug ataluren slowed the loss of walking ability in patients. The primary endpoint of the Phase 2b trial was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter (approximately 97 feet) difference in the average change in 6MWD when comparing the ataluren (10-, 10-, 20-mg/kg) and placebo arms. This result is consistent with the study hypothesis of a 30-meter difference and the average change in 6MWD observed in registration-directed trials of approved drugs for other diseases.
* Phase 2a Data nonsense mutation DBMD (nmDBMD): Data from Phase 2a clinical trials of ataluren in pediatric patients with nmDBMD show that administration of ataluren is associated with production of functional dystrophin. Ataluren treatment has also been associated with statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood.
* Phase 2a Data nonsense mutation CF (nmCF): Data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF show that administration of ataluren results in production of functional CFTR and statistically significant improvements in CFTR chloride channel function in the airways. Ataluren treatment was associated with reductions in cough frequency and improvements in pulmonary function tests.
* Adverse Events and Safety Profile: Across all clinical studies to date, including Phase 1 healthy-volunteer studies, ataluren has been generally well tolerated. Mean compliance has been >90% in all studies.
Grants
The development of ataluren has also been supported by grants from:
* Cystic Fibrosis Foundation
* Parent Project Muscular Dystrophy
* Muscular Dystrophy Association
* FDA’s Office of Orphan Products Development
*
National Center for Research Resources
* National Heart, Lung, and Blood Institute
The FDA has granted PTC124® (ataluren) Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DBMD due to nonsense mutations. PTC124® (ataluren) has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.
Partnership with Genzyme
PTC Therapeutics, Inc. and Genzyme Corporation have an exclusive collaboration to develop and commercialize ataluren. PTC will commercialize ataluren in the United States and Canada and Genzyme will commercialize ataluren in all other countries.
To receive status updates on ataluren, please visit the Contact Us page of the website and join our mailing list.
Patients, families and advocacy groups may also contact Ms. Diane Goetz, Director, Patient and Professional Relations, 866-282-5873 or 908-912-9256 or patientinfo@ptcbio.com.
Source: PTC Therapeutics
Note: Click the title to read more about PTC therapeutics and its developments.
Ataluren for Genetic Disorders
Ataluren (PTC124®) is an investigational drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation.
A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA) .
Click here to read Frequently Asked Questions about ataluren.
Translation of an mRNA into protein
Mechanism of Action
In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results.
Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional (eg, the CFTR protein in nmCF. the Factor VIII/Factor IX protein in nmHA/B or the dystrophin protein in nmDBMD ).
Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal.
Ataluren, taken orally, has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body.
Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimated that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. Besides nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD), nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA), these genetic disorders include a range of serious diseases across multiple therapeutic areas including, spinal muscular atrophy, lysosomal storage disorders, and some forms of cancer.
PTC124 Targets Genetic Disorders Caused by Nonsense Mutations
(Click the link above to read the article)
Genetic Testing
Ataluren has the potential to treat any genetic disorder caused by a nonsense mutation. Although current clinical trials involve only nonsense mutation CF and nonsense mutation HA/B, future trials are anticipated in other genetic disorders caused by a nonsense mutation. To determine whether a genetic disorder is caused by a nonsense mutation, patients require genetic testing. Genetic testing is done by a simple blood test that is ordered by a physician working in concert with a genetic lab.
Laboratories performing genetic testing vary by disorder and location. The NIH-funded website, www.genetest.org provides a listing of laboratories and contact information.
Ongoing Clinical Trials
* nmCF: PTC has initiated a longer-term, Phase 3 clinical study of ataluren in patients with nonsense mutation CF. The main goals of this study are to understand whether ataluren can improve how nmCF patients feel and function and whether the drug can safely be given over a long period. The trial is a multi-center, randomized, double-blind, placebo-controlled study.
* nmHA/B: PTC has initiated a Phase 2a clinical trial of ataluren in patients with nonsense mutation hemophilia type A and B (nmHA and nmHB). The trial is a multi-center, open label, dose escalation study. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation.
* nmMMA: PTC has initiated a Phase 2 clinical trial of ataluren in patients with nonsense mutation methylmalonic acidemia (nmMMA). The trial is a non-randomized, open-label trial. Its main goals are to understand whether ataluren can be tolerated and can decrease MMacid levels.
Completed Clinical Trials
*
Phase 2b Data nonsense mutation DBMD (nmDBMD): Final analyses of Phase 2b efficacy data suggest the investigational new drug ataluren slowed the loss of walking ability in patients. The primary endpoint of the Phase 2b trial was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter (approximately 97 feet) difference in the average change in 6MWD when comparing the ataluren (10-, 10-, 20-mg/kg) and placebo arms. This result is consistent with the study hypothesis of a 30-meter difference and the average change in 6MWD observed in registration-directed trials of approved drugs for other diseases.
* Phase 2a Data nonsense mutation DBMD (nmDBMD): Data from Phase 2a clinical trials of ataluren in pediatric patients with nmDBMD show that administration of ataluren is associated with production of functional dystrophin. Ataluren treatment has also been associated with statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood.
* Phase 2a Data nonsense mutation CF (nmCF): Data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF show that administration of ataluren results in production of functional CFTR and statistically significant improvements in CFTR chloride channel function in the airways. Ataluren treatment was associated with reductions in cough frequency and improvements in pulmonary function tests.
* Adverse Events and Safety Profile: Across all clinical studies to date, including Phase 1 healthy-volunteer studies, ataluren has been generally well tolerated. Mean compliance has been >90% in all studies.
Grants
The development of ataluren has also been supported by grants from:
* Cystic Fibrosis Foundation
* Parent Project Muscular Dystrophy
* Muscular Dystrophy Association
* FDA’s Office of Orphan Products Development
*
National Center for Research Resources
* National Heart, Lung, and Blood Institute
The FDA has granted PTC124® (ataluren) Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DBMD due to nonsense mutations. PTC124® (ataluren) has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.
Partnership with Genzyme
PTC Therapeutics, Inc. and Genzyme Corporation have an exclusive collaboration to develop and commercialize ataluren. PTC will commercialize ataluren in the United States and Canada and Genzyme will commercialize ataluren in all other countries.
To receive status updates on ataluren, please visit the Contact Us page of the website and join our mailing list.
Patients, families and advocacy groups may also contact Ms. Diane Goetz, Director, Patient and Professional Relations, 866-282-5873 or 908-912-9256 or patientinfo@ptcbio.com.
Source: PTC Therapeutics
Note: Click the title to read more about PTC therapeutics and its developments.
RETT SYNDROME IN A PETRI DISH: Rett Syndrome Research trust Interview series
On November 11th the high-profile journal Cell published a paper by Alysson Muotri, Ph.D. entitled A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. The stem cell field has seen amazing progress in the last few years. Induced Pluripotent Stem Cells (iPS cells) is an especially hot area because of the clinical implications. Simply put, iPS cells allow you to study diseased cells up close and personal through their entire lifecycle. Importantly, any deficits that are identified in the cells can be used as read-outs in drug screening endeavors.
Interviewed by Monica Coenraads
(Co-Founder, Trustee, Executive Director of RSRT)
I’ve had the pleasure of knowing Dr. Muotri for a number of years, in fact since his introduction to Rett about six years ago. He became interested in the disorder while doing his post-doc in the lab of Fred (Rusty) Gage at the Salk Institute in La Jolla, CA. Thankfully his interest has continued now that he is an independent investigator at UCSD.
Below is an excerpt from a conversation Dr. Muotri and Monica Coenraads had regarding his paper.
MC Dr. Muotri, congratulations on your Cell paper which has strong implications for drug development and therefore is of interest to anyone who loves a child with Rett Syndrome. I know this is a very hectic time so thank you for taking time out to speak with me.
I’m curious, what drew you to a science career?
AM I’ve always been interested in understanding how things work. I reasoned that science was the most obvious way to achieve that. You know that I’m from Brazil. I received my PhD in genetics from the University of São Paulo. I started off in the cancer biology field but quickly switched to neuroscience in 2002 when I moved to the Salk Institute. I was there for 6 years until I got my current position here at UCSD two years ago.
MC I’m assuming it was a significant switch moving into neuroscience from cancer biology.
AM Yes, it was a bit intimidating in the beginning because there was so much to learn. But I welcomed the challenge. And as it turned out my experiences from cancer were beneficial for my transition into neuroscience. For example, when I moved to Rusty’s lab one of the first observations we made was related to a phenomenon called transposons. I knew from my previous work that retrotransposons are very active in cancer cells and I remember discussing this with my neuroscience colleagues. Most of them were not very familiar with this phenomenon and assumed it was insignificant. My feeling was that if these transpositions were really happening in the brain it would be better to look at it closely because it could be involved in a new mechanism related to brain development.
MC Since retrotransposons are actually the topic of your next Rett paper coming out in Nature soon let me take a moment to give our readers a little background information.
Retrotransposons are sequences of DNA that move around and insert themselves into new positions within the genome. Barbara McClintock received the Nobel Prize in 1983 for her discovery of this phenomenon. Historically retrotransposons have been considered “junk DNA” because they occupy around 50% of the mammalian genome and do not have a clear function in the cell. It’s probably more likely that transposons have a biological function which remains, for the moment, unknown to us. Retrotransposons have been linked to disease.
Dr. Muotri, would you like to give us a glimpse into your upcoming paper that deals with retrotransposons in Rett Syndrome?
AM So the idea is that retrotransposons , which jump around inserting themselves into the genome, result in neurons, in the same individual, which are genetically different from each other. We observed that MECP2, the gene involved in Rett Syndrome, is a major repressor of this activity. Also, we determined that these jumping events are pretty much exclusive to the brain and MECP2 seems to be one of the gate keepers controlling the amount of the activity.
MC So in a brain that is deficient in the MeCP2 protein there would be increased jumping events?
AM That is right. It remains to be seen whether these extra events contribute to the symptoms of Rett or whether the brain simply compensates and manages to work around them. We are working on this question now.
MC Fascinating. I look forward to continuing our dialogue on this subject as your research progresses. Two high profile papers in one month – very impressive.
Now, getting back to iPS. This is a field that has seen amazing advances in a short period of time. Can you highlight for our readers the excitement surrounding these cells?
AM The dream of neuroscientists is to understand the early stages of a neurological disorder. Until recently we had two options to achieve this. One is to develop a mouse model that will hopefully recapitulate the symptoms seen in humans. Of course a limitation of a mouse model is that it’s a mouse and not a human – the brain of a human is so much more complex. The other option is post-mortem brain tissue. The problem is that at that stage the damage is already done and what you see is the end stage of a disease. To really study a disease it’s beneficial to have the most primitive cell line possible and then to coax these cells into a variety of different cell populations and to study what happens at various time points.
An important breakthrough happened a few years ago that has made this type of work very feasible. The Japanese group headed by Shinya Yamanaka surprised the world when they showed that you can reprogram cells that have already differentiated back to a more naïve state resembling a human embryonic stem cell. This allows us to capture the genome of a person, including any genetic mutations, and allows us to study the neurons and other cells of interest and see how a disease progresses and what changes happen at the molecular level.
MC In general the Rett field has relied on the mouse models as their standard assay. In terms of drug screening that’s a very expensive assay. Having iPS lines with MECP2 mutations gives scientists the ability to have a cellular assay to screen for therapeutics. Thousands, and in fact, hundreds of thousands of compounds can be efficiently and quickly screened in cell lines using either low or high throughput technologies.
Can you tell us about the phenotypes that you have identified in the cells. (a phenotype is an observable characteristic or trait)
AM One of the phenotypes was related to cell soma size (cell body) of a neuron. Just looking at neurons under the microscope we saw that Rett neurons are reduced in size by 10%. That might not seem like a big deal but when you consider the 3 dimensional structure of the neuron; a 10% reduction is very significant. So size was the simplest read-out that we found.
Another phenotype is related to the morphology of neurons. (Morphology is the study of the structure and form of an organism.) The idea to look at morphology was inspired by the reports over the last decade from post-mortem brain tissue in both people and animal models. We focused on the number of spine densities in neurons and we also saw a reduction. (A dendritic spine, or simply spine, is a small membranous protrusion from a neuron’s dendrite that typically receives input from a synapse.) We looked at neuronal networks and found deficiencies in their ability to communicate.
MC You made iPS cells with different MECP2 mutations. You found that the phenotypes were consistent among mutations. Can you elaborate?
AM Yes, the four different mutations we studied led to similar phenotypes. At least the phenotypes we looked at. We were convinced that this was a strong suggestion pointing to a loss of MeCP2 function. Thus, we knocked down MeCP2 expression from control neurons and obtained the same result. We then, restored the normal MeCP2 gene in Rett neurons, suppressing the phenotypes. In combination, these experiments suggest that MeCP2 is responsible for the alterations in Rett neurons. The fact that several MeCP2 mutants revealed a similar phenotype has clinical relevancy because it may indicate that a single drug may correct them all.
MC So the goal is to use these cells as a platform for drug screening.
AM Absolutely. As a proof of principle we added a growth factor, IGF1, to the cells. As you know a paper was published in PNAS in early 2009 showing that a compound similar to IGF1 improved some of the symptoms in mice so we decided to try it in our system. We found that IGF1 corrected the phenotype, in fact it over-corrected. The over-correction is something that needs to be considered in terms of the clinical trial, a proper dose tuning in each patient is desirable. Also, something to keep in mind is that while I put IGF1 directly into the cells in the clinical trial the IGF1 has to get into the brain and we know that that doesn’t happen as much as we would like.
The other drug we tried is gentamicin , an antibiotic that has the ability to “read through” premature stop codons (nonsense mutations that end in X, such as 255X, 168X) . We found that gentamicin restored levels of the MeCP2 and phenotypically rescued the cells.
MC That is pretty interesting especially in light of the fact that read through drugs act by substituting the stop codon with a random amino acid. So in effect they swap out one mutation for another.
AM We checked that and found that the protein level was normal but there was no way for us to see what mutation was inserted. Part of the new protein that is synthesized in the presence of gentamicin, is probably correct and we believe that is exactly what is reverting the phenotypes.
MC It’s important to note that gentamicin is highly toxic and doesn’t cross the blood brain barrier very well either so this is not a drug that can be used now for the treatment of Rett Syndrome. There are however other drugs with similar modes of action that being tested in animal models.
But the take home message from your data is that iPS cell lines are an in vitro model system for Rett Syndrome and can be utilized in a drug screening platform. What are next steps to utilize the iPS lines as a platform for drug screening?
AM The next step is to scale this up and that is not easy to do. Because the experiments are very sensitive to variables and there are many steps during the conversion of the iPS cells to neurons. Thus, we need to systematically validate all the variables and make the system as robust as possible. Finally, we need to choose the appropriate read-outs (the cellular phenotypes) we would like to use. It is important to design these experiments carefully so one doesn’t lose time with false positives. My lab was recently awarded a CIRM grant (California Institute for Regenerative Medicine) exactly to optimize these steps, so I would like to start this as soon as possible. Finally, I would like to test libraries of drugs that previously failed clinical trials for other diseases. Drug repositioning, as this concept is called, is attractive because repurposed drugs can bypass much of the early cost and time needed to bring a drug to market.
MC I found your paper very encouraging for a number of reasons. Firstly, your data continues to confirm and validate the concept that Rett is reversible. Secondly, you showed that the iPS platform can be used for drug screening. Thirdly, your data suggests that while there may be many mutations in MECP2, they may share common phenotypes. That may be an important issue in terms of treatment strategies.
Dr. Muotri, I’m sure I speak for every Rett family who reads this interview … we wish you great luck and god speed in your work.
Source: Rett Syndrome Research Trust (RSRT)
Note: Click on the title the full interview and video
Interviewed by Monica Coenraads
(Co-Founder, Trustee, Executive Director of RSRT)
I’ve had the pleasure of knowing Dr. Muotri for a number of years, in fact since his introduction to Rett about six years ago. He became interested in the disorder while doing his post-doc in the lab of Fred (Rusty) Gage at the Salk Institute in La Jolla, CA. Thankfully his interest has continued now that he is an independent investigator at UCSD.
Below is an excerpt from a conversation Dr. Muotri and Monica Coenraads had regarding his paper.
MC Dr. Muotri, congratulations on your Cell paper which has strong implications for drug development and therefore is of interest to anyone who loves a child with Rett Syndrome. I know this is a very hectic time so thank you for taking time out to speak with me.
I’m curious, what drew you to a science career?
AM I’ve always been interested in understanding how things work. I reasoned that science was the most obvious way to achieve that. You know that I’m from Brazil. I received my PhD in genetics from the University of São Paulo. I started off in the cancer biology field but quickly switched to neuroscience in 2002 when I moved to the Salk Institute. I was there for 6 years until I got my current position here at UCSD two years ago.
MC I’m assuming it was a significant switch moving into neuroscience from cancer biology.
AM Yes, it was a bit intimidating in the beginning because there was so much to learn. But I welcomed the challenge. And as it turned out my experiences from cancer were beneficial for my transition into neuroscience. For example, when I moved to Rusty’s lab one of the first observations we made was related to a phenomenon called transposons. I knew from my previous work that retrotransposons are very active in cancer cells and I remember discussing this with my neuroscience colleagues. Most of them were not very familiar with this phenomenon and assumed it was insignificant. My feeling was that if these transpositions were really happening in the brain it would be better to look at it closely because it could be involved in a new mechanism related to brain development.
MC Since retrotransposons are actually the topic of your next Rett paper coming out in Nature soon let me take a moment to give our readers a little background information.
Retrotransposons are sequences of DNA that move around and insert themselves into new positions within the genome. Barbara McClintock received the Nobel Prize in 1983 for her discovery of this phenomenon. Historically retrotransposons have been considered “junk DNA” because they occupy around 50% of the mammalian genome and do not have a clear function in the cell. It’s probably more likely that transposons have a biological function which remains, for the moment, unknown to us. Retrotransposons have been linked to disease.
Dr. Muotri, would you like to give us a glimpse into your upcoming paper that deals with retrotransposons in Rett Syndrome?
AM So the idea is that retrotransposons , which jump around inserting themselves into the genome, result in neurons, in the same individual, which are genetically different from each other. We observed that MECP2, the gene involved in Rett Syndrome, is a major repressor of this activity. Also, we determined that these jumping events are pretty much exclusive to the brain and MECP2 seems to be one of the gate keepers controlling the amount of the activity.
MC So in a brain that is deficient in the MeCP2 protein there would be increased jumping events?
AM That is right. It remains to be seen whether these extra events contribute to the symptoms of Rett or whether the brain simply compensates and manages to work around them. We are working on this question now.
MC Fascinating. I look forward to continuing our dialogue on this subject as your research progresses. Two high profile papers in one month – very impressive.
Now, getting back to iPS. This is a field that has seen amazing advances in a short period of time. Can you highlight for our readers the excitement surrounding these cells?
AM The dream of neuroscientists is to understand the early stages of a neurological disorder. Until recently we had two options to achieve this. One is to develop a mouse model that will hopefully recapitulate the symptoms seen in humans. Of course a limitation of a mouse model is that it’s a mouse and not a human – the brain of a human is so much more complex. The other option is post-mortem brain tissue. The problem is that at that stage the damage is already done and what you see is the end stage of a disease. To really study a disease it’s beneficial to have the most primitive cell line possible and then to coax these cells into a variety of different cell populations and to study what happens at various time points.
An important breakthrough happened a few years ago that has made this type of work very feasible. The Japanese group headed by Shinya Yamanaka surprised the world when they showed that you can reprogram cells that have already differentiated back to a more naïve state resembling a human embryonic stem cell. This allows us to capture the genome of a person, including any genetic mutations, and allows us to study the neurons and other cells of interest and see how a disease progresses and what changes happen at the molecular level.
MC In general the Rett field has relied on the mouse models as their standard assay. In terms of drug screening that’s a very expensive assay. Having iPS lines with MECP2 mutations gives scientists the ability to have a cellular assay to screen for therapeutics. Thousands, and in fact, hundreds of thousands of compounds can be efficiently and quickly screened in cell lines using either low or high throughput technologies.
Can you tell us about the phenotypes that you have identified in the cells. (a phenotype is an observable characteristic or trait)
AM One of the phenotypes was related to cell soma size (cell body) of a neuron. Just looking at neurons under the microscope we saw that Rett neurons are reduced in size by 10%. That might not seem like a big deal but when you consider the 3 dimensional structure of the neuron; a 10% reduction is very significant. So size was the simplest read-out that we found.
Another phenotype is related to the morphology of neurons. (Morphology is the study of the structure and form of an organism.) The idea to look at morphology was inspired by the reports over the last decade from post-mortem brain tissue in both people and animal models. We focused on the number of spine densities in neurons and we also saw a reduction. (A dendritic spine, or simply spine, is a small membranous protrusion from a neuron’s dendrite that typically receives input from a synapse.) We looked at neuronal networks and found deficiencies in their ability to communicate.
MC You made iPS cells with different MECP2 mutations. You found that the phenotypes were consistent among mutations. Can you elaborate?
AM Yes, the four different mutations we studied led to similar phenotypes. At least the phenotypes we looked at. We were convinced that this was a strong suggestion pointing to a loss of MeCP2 function. Thus, we knocked down MeCP2 expression from control neurons and obtained the same result. We then, restored the normal MeCP2 gene in Rett neurons, suppressing the phenotypes. In combination, these experiments suggest that MeCP2 is responsible for the alterations in Rett neurons. The fact that several MeCP2 mutants revealed a similar phenotype has clinical relevancy because it may indicate that a single drug may correct them all.
MC So the goal is to use these cells as a platform for drug screening.
AM Absolutely. As a proof of principle we added a growth factor, IGF1, to the cells. As you know a paper was published in PNAS in early 2009 showing that a compound similar to IGF1 improved some of the symptoms in mice so we decided to try it in our system. We found that IGF1 corrected the phenotype, in fact it over-corrected. The over-correction is something that needs to be considered in terms of the clinical trial, a proper dose tuning in each patient is desirable. Also, something to keep in mind is that while I put IGF1 directly into the cells in the clinical trial the IGF1 has to get into the brain and we know that that doesn’t happen as much as we would like.
The other drug we tried is gentamicin , an antibiotic that has the ability to “read through” premature stop codons (nonsense mutations that end in X, such as 255X, 168X) . We found that gentamicin restored levels of the MeCP2 and phenotypically rescued the cells.
MC That is pretty interesting especially in light of the fact that read through drugs act by substituting the stop codon with a random amino acid. So in effect they swap out one mutation for another.
AM We checked that and found that the protein level was normal but there was no way for us to see what mutation was inserted. Part of the new protein that is synthesized in the presence of gentamicin, is probably correct and we believe that is exactly what is reverting the phenotypes.
MC It’s important to note that gentamicin is highly toxic and doesn’t cross the blood brain barrier very well either so this is not a drug that can be used now for the treatment of Rett Syndrome. There are however other drugs with similar modes of action that being tested in animal models.
But the take home message from your data is that iPS cell lines are an in vitro model system for Rett Syndrome and can be utilized in a drug screening platform. What are next steps to utilize the iPS lines as a platform for drug screening?
AM The next step is to scale this up and that is not easy to do. Because the experiments are very sensitive to variables and there are many steps during the conversion of the iPS cells to neurons. Thus, we need to systematically validate all the variables and make the system as robust as possible. Finally, we need to choose the appropriate read-outs (the cellular phenotypes) we would like to use. It is important to design these experiments carefully so one doesn’t lose time with false positives. My lab was recently awarded a CIRM grant (California Institute for Regenerative Medicine) exactly to optimize these steps, so I would like to start this as soon as possible. Finally, I would like to test libraries of drugs that previously failed clinical trials for other diseases. Drug repositioning, as this concept is called, is attractive because repurposed drugs can bypass much of the early cost and time needed to bring a drug to market.
MC I found your paper very encouraging for a number of reasons. Firstly, your data continues to confirm and validate the concept that Rett is reversible. Secondly, you showed that the iPS platform can be used for drug screening. Thirdly, your data suggests that while there may be many mutations in MECP2, they may share common phenotypes. That may be an important issue in terms of treatment strategies.
Dr. Muotri, I’m sure I speak for every Rett family who reads this interview … we wish you great luck and god speed in your work.
Source: Rett Syndrome Research Trust (RSRT)
Note: Click on the title the full interview and video
Monday, November 15, 2010
Women of the year 2010: Julia Roberts
Julia Roberts: The Class Act
She is a Woman of the Year because: “There are not a lot of people who can do everything she does, and be brilliant, and be gorgeous, and raise all those children. Formidable, my dear. Bravo.”
—Joanne Woodward, actress
November 1, 2010
by Susan Dominus
You have to admire that Julia Roberts arrives at an interview in the kind of standard-issue black pants that mothers rely on when they want to look presentable. Wearing the barest hint of makeup, she’s soon chatting about the challenge of running a house with three kids—six-year-old twins Hazel and Phinnaeus, and three-year-old Henry. “Trust me,” she confides, “some weeks are cleaner than other weeks.”
Not that she’s had much time lately to worry about the housecleaning. Her 2010 has been huge. She’s graced countless magazine covers and TV shows on behalf of her blockbuster Eat, Pray, Love; she produced a documentary on the power of motherhood that will air on Oprah’s OWN network in January; and she filmed her next sure-to-be hit, Larry Crowne, with pal Tom Hanks.
Despite her successes, though, Roberts says, “It’s all about the home.” Turns out one of the world’s biggest female movie stars (collective box office: more than $2 billion) is an eco-sensitive earth mother who composts and drives a tractor at her New Mexico ranch. At 43, the Oscar winner chooses roles that allow her to spend quality time with her family—proof, as she’s said, that “becoming famous doesn’t make you crazy.” Once called the Hillary of Hollywood for her trailblazing—she was the first actress to get more than $20 million for a film—Roberts has used that money and clout for good. Since 1997 she’s supported Paul Newman’s Hole in the Wall Gang camp for children with grave illnesses. She also campaigns to fund research for Rett Syndrome (a neurodevelopmental disorder that can destroy kids’ ability to walk and speak) and serves on the board of Earth Biofuels, which promotes renewable energy.
But it’s Roberts’ unique, lit-from-within quality that’s made her everyone’s favorite screen icon. In the words of Eat, Pray, Love author Elizabeth Gilbert, “The only other job she could have would be professional fairy.” Well, she did once play Tinkerbell.
Source: Glamour
She is a Woman of the Year because: “There are not a lot of people who can do everything she does, and be brilliant, and be gorgeous, and raise all those children. Formidable, my dear. Bravo.”
—Joanne Woodward, actress
November 1, 2010
by Susan Dominus
You have to admire that Julia Roberts arrives at an interview in the kind of standard-issue black pants that mothers rely on when they want to look presentable. Wearing the barest hint of makeup, she’s soon chatting about the challenge of running a house with three kids—six-year-old twins Hazel and Phinnaeus, and three-year-old Henry. “Trust me,” she confides, “some weeks are cleaner than other weeks.”
Not that she’s had much time lately to worry about the housecleaning. Her 2010 has been huge. She’s graced countless magazine covers and TV shows on behalf of her blockbuster Eat, Pray, Love; she produced a documentary on the power of motherhood that will air on Oprah’s OWN network in January; and she filmed her next sure-to-be hit, Larry Crowne, with pal Tom Hanks.
Despite her successes, though, Roberts says, “It’s all about the home.” Turns out one of the world’s biggest female movie stars (collective box office: more than $2 billion) is an eco-sensitive earth mother who composts and drives a tractor at her New Mexico ranch. At 43, the Oscar winner chooses roles that allow her to spend quality time with her family—proof, as she’s said, that “becoming famous doesn’t make you crazy.” Once called the Hillary of Hollywood for her trailblazing—she was the first actress to get more than $20 million for a film—Roberts has used that money and clout for good. Since 1997 she’s supported Paul Newman’s Hole in the Wall Gang camp for children with grave illnesses. She also campaigns to fund research for Rett Syndrome (a neurodevelopmental disorder that can destroy kids’ ability to walk and speak) and serves on the board of Earth Biofuels, which promotes renewable energy.
But it’s Roberts’ unique, lit-from-within quality that’s made her everyone’s favorite screen icon. In the words of Eat, Pray, Love author Elizabeth Gilbert, “The only other job she could have would be professional fairy.” Well, she did once play Tinkerbell.
Source: Glamour
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