IRSF announces funding of first clinical trial with disease-modifying therapy for Rett syndrome

(Cincinnati, OH) - Today, the International Rett Syndrome Foundation announced that it will provide $200,000 in 2009 to support a newly proposed clinical trial with a growth-factor based treatment for Rett Syndrome. The study will be carried out by a team of clinical trials specialists at the Boston Children's Hospital, led by Dr. Omar Khwaja MD, PhD and will be the first potentially disease modifying therapy ever to be tested in Rett syndrome patients. Investigators will test a drug called Increlex. This is an engineered form of the human protein Insulin-like Growth Factor-1, an FDA approved drug for children with short stature due to severe Primary IGF-1 deficiency. Preliminary evidence in animal models of Rett syndrome has recently suggested that targeting the IGF-1 signaling axis may provide a potential avenue for therapy.

"We are pleased to announce the funding of this groundbreaking new clinical study which presents a novel therapeutic strategy for the treatment of Rett syndrome" said Dr. Antony Horton Chief Scientific Officer at the International Rett Syndrome Foundation. "This study will be carried out by a collaborative network of leading clinicians and neuroscientists in some of the World's most prestigious research institutes at the cutting edge of biomedical research. Through our funding of this study we demonstrate our commitment to moving forward the most advanced treatments to prevent, treat and ultimately reverse Rett syndrome".

Dr. Omar Khwaja, principal investigator on the study commented further "Since the 2007 studies which demonstrated potential reversal of Rett syndrome in animal models, there has been a paradigm shift in our thinking about ways to treat this devastating condition. Our pilot study will utilize an existing FDA approved medication, seeking to boost growth of synapses in the brain of patients with Rett syndrome".

Increlex will be provided gratis by Tercica Inc., A Subsidiary of the IPSEN Group, who have reviewed and approved the trial through their internal scientific review board.

Dr. Khwaja and his team have also secured additional funding for this clinical trial through a grant provided by Harvard University's Catalyst Pilot Awards for Clinical Translational Research

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IRSF provides careful due diligence on all clinical studies involving patients with Rett syndrome since safety is of paramount importance. We accomplish this through a rigorous peer-review process, drawing on the external advice and expertise of leading clinical trials specialists in the fields of Rett syndrome, Autism, Pediatric Neurology and other relevant disciplines as appropriate.

About Rett Syndrome

Rett syndrome (RTT), a brain disorder affecting development in childhood, has been identified almost exclusively in females. RTT results in severe movement and communication problems following apparently normal development for the first six months of life. The characteristic features include loss of speech and purposeful hand use, occurrence of repetitive hand movements, abnormal walking, abnormal breathing, and slowing in the rate of head growth. Current treatment for girls with RTT includes physical and occupational therapy, speech therapy, and medication for seizures. No cure for Rett syndrome is known. In 2008, researchers heralded a major breakthrough by reversing RTT symptoms in mouse models. Rett syndrome is recognized as the "Rosetta Stone" of other neurological disorders, with genetic links to other disorders like autism and schizophrenia.

About the International Rett Syndrome Foundation

IRSF is the world's leading private funder of basic and clinical Rett syndrome research, funding over $18M in research grants and quality research programs to date. Annually, IRSF hosts the world's largest gathering of global Rett researchers and clinicians to establish research direction and priorities while exchanging ideas and the most recent information. IRSF is the most comprehensive non-profit organization dedicated to providing thorough and accurate information about Rett syndrome, offering informational and emotional family support, and stimulating research aimed at accelerating treatments and a cure for Rett syndrome and related disorders. To learn more about IRSF and Rett syndrome, visit www.rettsyndrome.org or call IRSF at 1-800-818-RETT.

About Boston Children's Hospital

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.

Contact: Mary Joyce Griffin
mgriffin@rettsyndrome.org
513-870-4378
International Rett Syndrome Foundation


Public release date: 21-Sep-2009

Another gene found for Rett syndrome

New research has revealed another gene for Rett syndrome which could lead to new treatments for the disorder. A research project by scientists from Australia and Israel has identified a genetic variation that influences the severity of symptoms in Rett syndrome. The scientists have established a correlation between the severity of clinical symptoms and a common brain-derived neurotrophic factor (BDNF) polymorphism and they say patients with the normal BDNF genetic variant had less severe symptoms, with later onset and frequency of seizures. Dr Helen Leonard from the Australian Rett Syndrome Study at the Telethon Institute for Child Health Research, says the finding was exciting in that it identifies a potential new target for treatment of the debilitating neurological disorder. Dr Leonard says previously it was known that there is a wide range in the onset and severity of symptoms in patients with Rett syndrome but it was difficult to give families a firm idea of how the disorder would progress and the new information is potentially helpful in predicting the clinical progression, but importantly, offers another area to explore for potential therapies. In the study, clinical information and DNA samples were gathered from 125 patients from the Australian Rett Syndrome Database and an Israeli cohort coordinated by Dr Bruria Ben Zeev at the Safra Pediatric Hospital, Sheba Medical Centre, Sackler School of Medicine, Tel Aviv. Professor John Christodoulou, from the NSW Centre for Rett Syndrome Research at the Children's Hospital at Westmead in Sydney and Dr Eva Gak from the Sagol Neuroscience Center at the Sheba Medical Centre carried out the genetic testing and say the new findings have established a correlation between the severity of clinical symptoms and BDNF polymorphism. Dr Christodoulou says those patients with the normal BDNF genetic variant had less severe symptoms, with later onset and frequency of seizures. He says they must now establish the nature of the interaction between MECP2 and BDNF and if it is possible to stimulate BDNF within patients with Rett syndrome, there is a chance that the onset of seizures can be delayed and some of the more debilitating aspects of the disorder reduced. Rett syndrome is a childhood neurodevelopmental disorder which almost always only affects females. Although Rett syndrome is a genetic disorder less than 1% of recorded cases are inherited or passed from one generation to the next - most cases are sporadic, which means the mutation occurs randomly and is not inherited. Initially Children with Rett's develop and grow normally but gradually symptoms appear which include a loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. The way Rett syndrome progresses, including the age it starts and the severity of symptoms, varies from child to child; mental and physical symptoms gradually appear such as a loss of muscle tone and as the syndrome progresses, the child loses purposeful use of their hands and the ability to speak - other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing and this period of regression is sometimes sudden. Another symptom, apraxia - the inability to perform motor functions - is perhaps the most severely disabling feature of Rett syndrome, interfering with every body movement, including eye gaze and speech and children with Rett syndrome often exhibit autistic-like behaviours in the early stages. Other symptoms may include toe walking, sleep problems, wide-based gait, teeth grinding and difficulty chewing, slowed growth, seizures, cognitive disabilities, and breathing difficulties while awake such as hyperventilation, apnoea (breath holding), and air swallowing. Rett syndrome is caused by mutations in the MECP2 gene, which is found on the X chromosome and up to 80% of girls with Rett syndrome have the MECP2 genetic mutation. The remaining 20 to 30% of cases are suspected to be caused by mutations in other parts of the gene or by genes yet to be identified. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight; special academic, social, vocational, and support services may also be required in some cases. Despite the difficulties with symptoms, most individuals with Rett syndrome continue to live well into middle age and beyond. The finding is published in the international journal Neurology. 6a03bc68-77de-40cd-a513-b9c9db839e79|0|.0 Source: Medical Condition News http://www.news-medical.net/news/2009/04/22/48627.aspx

Novel Approach To Treating Rett Syndrome Under Development

A paper published in Nature Neuroscience reveals the presence of methyl CpG binding protein 2 (MeCP2) in glia. MeCP2 is a protein associated with a variety of neurological disorders, including Rett Syndrome, the most physically disabling of the autism spectrum disorders. The researchers show that MeCP2-deficient astrocytes (a subset of glia) stunt the growth of neighboring neurons. Remarkably, these neurons can recover when exposed to normal glia in culture. The discovery was made by Gail Mandel, Ph.D. of the Vollum Institute at Oregon Health and Science University and a Howard Hughes Medical Institute investigator and Nurit Ballas, Ph.D., a research associate, at the time, in the Mandel lab at the State University of New York at Stony Brook. Dr. Mandel is a scientific advisor of the Rett Syndrome Research Trust (RSRT) a recently formed nonprofit organization intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders. 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. Most live into adulthood, and require total, round the clock care. Individuals with Rett and their families suffer the emotional and financial cost of the wide range of symptoms and the ongoing struggles to address them. Glial cells, which reside throughout the nervous system, comprise the vast majority (90%) of cells in the brain. Glia support and interact with neurons in innumerable ways, from providing the structural underpinnings and guidance of axons and dendrites (the neuronal processes that carry information), to creating protective insulation for axons. These and other glial functions are essential to the health of neurons. Since MECP2 is located on the X chromosome, girls with Rett Syndrome are mosaic: cells with a healthy copy of the gene lie side by side with cells that have the mutated version. Mandel and colleagues found that MECP2- deficient astrocytes could not sustain normal neuronal growth. In fact, their experiments suggest that MeCP2-deficient astrocytes secrete a toxic factor that impacts the entire neighborhood of neurons, including neurons with wildtype (normal) MECP2. Conversely, they found that wildtype astrocytes could restore the stunted growth of MeCP2-deficient neurons. This finding supports the 2007 Science publication by Professor Adrian Bird showing reversal of Rett symptoms in adult mouse models of the disorder. Results from ongoing in vivo mouse studies deleting MeCP2 in glia are promising in terms of supporting the culture studies. “This new study adds to the growing body of evidence that glial cells are critically important contributors to neurological diseases and therefore attractive targets for drug development,” said Ben Barres, Professor and Chair of the Department of Neurobiology at Stanford University and a glial cell expert. Recent studies from multiple groups, including the lab of Dr. Tom Maniatis, a neurodegenerative disease researcher at Harvard University, have implicated glia in Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis – ALS), a devastating neurodegenerative disorder that leads to the death of motor neurons and total paralysis. “In Rett Syndrome, faulty glia seem to poison neurons, inhibiting growth; in ALS glia appear to release a toxic factor that kills motor neurons.” Maniatis stated that “studies of the role of glia in a broad spectrum of neuronal diseases should lead to exciting advances in understanding disease mechanisms.” “Dr. Mandel’s sharp insights have given the scientific community an entirely new way to think about treating Rett Syndrome. One could envision a scenario where halting the secretion of this potential toxic factor could restore health, in particular to the MECP2 positive neurons, which could bring about amelioration of symptoms. I look forward to her lab’s continued contributions as we explore the therapeutic implications of her research,” comments Monica Coenraads, Executive Director of RSRT and parent of a child with the disorder. Other people who worked on the project include Daniel T. Lioy of the Vollum Institute and Christopher Grunseich, M.D. while at the State University of New York at Stony Brook. Nurit Ballas is now a Research Associate Professor in the Department of Biochemistry and Cell Biology at Stony Brook. This project was funded in part by the NIH, HHMI and IRSF. SOURCE: RETT SYNDROME RESEARCH TRUST The ScienceDaily http://www.sciencedaily.com/releases/2009/02/090223094711.htm