Highlights of RSRT’s 2014 awards:
- Funding of $1.3 million was awarded to Case Western Reserve University and the Cleveland Clinic for a Phase 2 clinical trial of low-dose ketamine for the treatment of Rett Syndrome. Ketamine, a drug that has historically been used for sedation and anesthesia, has recently generated much enthusiasm for its ability to rapidly reverse major depression at low, sub-anesthetic, doses. Studies undertaken by David Katz, Ph.D., showed that low-dose ketamine can reverse deficits in brain activity in mouse models of Rett Syndrome in conjunction with significant improvements in neurological function, including breathing. This trial will determine the effect of single doses of ketamine on breathing abnormalities and other Rett Syndrome symptoms.The study is being led by David Katz, Ph.D., Professor of Neurosciences and Psychiatry at Case Western Reserve University School of Medicine and Daniel I. Sessler, M.D., Michael Cudahy Professor and Chair, Department of Outcomes Research at the Cleveland Clinic.
“This trial evolved as a dynamic collaboration among basic scientists, clinicians, and clinical trialists including expert advisers recruited by RSRT. We are grateful to RSRT for fostering this collaborative spirit and providing the support necessary to make this trial a reality.”
- Aleksandra Djukic, M.D., Ph.D., medical director of the Tri-State Rett Syndrome Center at the Children’s Hospital at Montefiore was awarded $403,000 to conduct a Phase 2 clinical trial of lovastatin, a cholesterol lowering medication. The scientific basis for this trial stems from experiments conducted in the lab of mouse geneticist, Monica Justice, Ph.D., who identified the cholesterol pathway as a potential avenue to improve Rett symptoms. The trial will determine the effect of lovastatin on gait, respiratory function, cognition and other Rett symptoms including the severity of the disease.In addition, Dr. Djukic recently concluded a Phase 2 trial testing safety and effectiveness of a multiple sclerosis drug, copaxone, in treating Rett Syndrome. The data is currently being analyzed.
“Cholesterol is vitally important for brain function. In fact, although the brain is only 2-3% of total body weight, it contains and makes 25% of the body’s cholesterol. Dr. Justice’s work suggests that elevated cholesterol levels in the brain may play a role in Rett symptoms. Our trial will test the hypothesis that reducing cholesterol in the brain will lead to symptom improvement.”
The ketamine and lovastatin trials will begin recruitment shortly. We will send you notification as soon as they are ready to proceed and will provide detailed information on the RSRT website.
- Individuals with Rett display a broad spectrum of symptom severity. Some girls can run, have a degree of hand use and can speak in short sentences while others cannot even sit or hold their head up. One reason for this variation is the child’s own unique genetic makeup. In other words, we’ve learned that variations in other genes have an impact on the severity of the Rett mutation. Monica Justice, Head and Senior Scientist in the Genetics & Genome Biology program at The Hospital for Sick Children in Toronto, has undertaken a screen to identify these other, modifying genes that potentially impact the severity of Rett symptoms. The first suppressor gene she identified, squalene epoxidase, led to the lovastatin trial described above. The screen is currently at the halfway point, with 12 modifiers identified. RSRT has awarded Dr. Justice $716,000 in additional funding to complete the screen. This brings RSRT’s total commitment to the project to $2.3 million.
“Monica Coenraads approached me a number of years ago asking how I would identify modifiers. I thought that an unbiased suppressor screen using a mouse supermutagen would be the most effective approach, and was timely with the advent of new genome sequencing technologies. Such an approach was considered very risky, requiring funding through a forward-looking organization such as the RSRT. It has been extremely rewarding to move from the development of a concept…to isolating modifiers that were unexpected…to a clinical trial. Our ongoing screen is much easier and quicker now as technologies advance. My hope is that many more trials will come from the continuing screen.”
- Two additional projects are aimed at awakening a healthy but silenced back-up copy of the mutated Rett gene. If the flawed gene could be replaced by reawakening its silenced counterpart we could conceivably reverse Rett symptoms.Currently pursuing this approach with RSRT funding are labs at the University of North Carolina at Chapel Hill, the University of Massachusetts, Harvard University, and Fred Hutchinson Cancer Research Center. These labs are now in regular communication because of RSRT’s strong belief in and facilitation of collaborative research models that encourage the sharing of data, cell lines and compounds.RSRT has awarded additional funding totaling $755,000 to two projects ongoing in the labs of Jeannie Lee, Ph.D., of Harvard and Antonio Bedalov, M.D., Ph.D., of Fred Hutchinson to aggressively pursue this work.
- RSRT funding will allow David Katz to purse research on the drug, LM22A-4, towards an application to the FDA for an IND (Investigational New Drug).
- Successful fundraising on the part of the MECP2 Duplication Syndrome community facilitated two awards totaling $644,065 to Huda Zoghbi, M.D., Professor in the Departments of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience at Baylor College of Medicine and director of the Jan and Dan Duncan Neurological Research Institute. The funds will support two strategic approaches to treating the disorder.
“We are very excited to receive support for exploring two different strategies to reduce MeCP2 levels. The two strategies are complementary, one involving genetic screens in human cells to find potential targets that can be druggable with a pharmaceutical agent, while the other employs antisense oligonucleotides developed by Isis pharmaceuticals and designed to reduce MeCP2 levels directly.”
Our partners in supporting this work are parents’ organizations worldwide including Reverse Rett (UK), Rett Syndrome Research & Treatment Foundation (Israel), Skye Wellesley Foundation (UK), Rett Syndrome & CDKL5 Ireland, Rett Syndrom Deutschland, Stichting Rett Syndrome (Holland); and American organizations, Girl Power 2 Cure, Eva Fini Fund at RSRT, Kate Foundation for Rett Syndrome Research, Rocky Mountain Rett Association, Anastasi Fund, Claire’s Crusade, New Jersey Rett Syndrome Association, Rett Syndrome Association of Massachusetts, and the MECP2 Duplication Syndrome Fund at RSRT.