The National MPS Society has allocated $335,000 in grant funding for 2016 which includes the second year funding for grants awarded in 2015. The funding the Society provides has been and continues to be critical as we move forward with our mission to find cures for MPS and ML. We received many letters of intent from researchers around the world for research grants. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from researchers. Two new grants were chosen for MPS IVA and for MPS VII. Additionally, $100,000 of funds raised were through the Million Dollar Bike Ride Effort and these funds have been allocated through the University of Pennsylvania for MPS Research grants.
The Board of Directors allocated $30,000 through the Fundraising Directive Program. The family who raised these funds requested work be continued with Dr. Haiyan Fu of the Research Institute at Nationwide Children’s Hospital for gene therapy approach for advanced MPS II via AAV9 vectors.
The Society also provided $25,000 to support the Lysosomal Disease Network’s NIH grant research goals. The funding is designed for the Neuroimaging Core, which will benefit the four MPS projects. The Society also provided $5,000 in partnership with the Ryan Foundation for an MPS I project.
In the fourth quarter of 2016 the Society raised an additional $150,000 in research funds to be awarded for two new projects in the first quarter of 2017. $135,000 will be awarded to Dr. Charbel Moussa of Georgetown University for an MPS IIIA drug repurposing project and $30,000 will be awarded in a partnership grant with the ISMRD (International Society for Mannosidosis and Related Diseases) for novel ML gene therapy research with Dr. Stephen Gray at UNC Hospital in partnership with Dr. Charles Vite at the University of Pennsylvania.
Dr. Kim Hemsley
South Australia Health and Medical Research Institute
Adelaide, South Australia
“AAV2/8-mediated expression of modified sulphamidase, liver targeting for improved secretion and brain delivery in IIIA Huntaway dog.”
This is a pre-clinical trial of a new gene therapy approach for Sanfilippo syndrome type A. The therapy treats brain disease in mice with Sanfilippo type A (MPS IIIA; Sorrentino et al., 2013 EMBO Mol Med 5: 1-16), however – mice have very small brains, and so before advancing this treatment into human clinical trials, it is import ant to detennine whether the therapy is effective at treating a much larger brain – that of the Huntaway dog model of this disorder. Dogs will be treated at an age when brain disease has already started, but is not maximal. Treatment involves them getting an injectio n into the bloodstream. Then, how well the treatment is able to get rid of the accumulated heparan sulphate in the brain (and other organs), and how effectively it normalises other aspects of brain disease, will be assessed. Safety aspects of the therapy will also be examined. It is critical that all of this information is gathered before the treatment is given to children with Sanfilippo syndrome type A. A modified form of this treatment approach could also be used for other brain diseases.
Dr. Kazuki Sawamoto, Dr. Shunji Tomatsu
Nemours/Alfred I. duPont Hospital for Children
“Gene Therapy for MPS IVA”
Mucopolysaccharidosis IVA (MPS IVA: Morquio A syndrome) is caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme progressively causes accumulation of the glycosaminoglycans keratan sulfate and chondroitine-6-sulfate in multiple tissues (especially bone, cartilage, heart valves, and cornea), and leads to a unique form of skeletal dysplasia. Enzyme replacement therapy (ERT) for MPS IVA has been recently approved by the FDA. However, weekly ERT has a limited impact on bone abnormalities, and current therapies do not relieve skeletal symptoms in MPS IVA. Therefore, a novel therapy for MPS IVA is required to prevent or rescue the skeletal abnormalities. Gene therapy is a regenerative medicine that is expected to provide a one-time permanent treatment since the active enzyme is secreted continuously by transduced cells into the circulation. As yet, there are no in vivo reports on MPSIVA gene therapy. To assess the effect of gene therapy on skeletal disorders of MPS IVA, we will evaluate the effect of two gene vectors to replace the deficient enzyme in a MPS IVA mouse model. We hypothesize that the proposed gene vectors will have a significant impact on bone and cartilage lesions in MPS IVA.
Dr. Lachlan J. Smith
University of Pennsylvania
“Therapeutic Targeting of Wnt/β-Catenin Signaling to Improve Bone Formation in MPS VII”
Skeletal disease is prevalent in most mucopolysaccharidosis (MPS) subtypes, particularly in the spine, where vertebral dysplasia leads to progressive def01mity and spinal cord compression. Resulting pain and paralysis significantly diminish patient quality of life and increase m01iality. MPS VII patients exhibit severe spine disease for which there are currently no effective treatments. Previously, using the natural-occurring canine model of MPS VII, we established that vertebral bone formation is delayed, non-uniform and incomplete during postnatal growth. Wnt/B-catenin signaling is a crucial positive regulator of bone formation and our preliminary data suggests impaired activation of this pathway coincident with the earliest manifestations of bone disease in MPS VII dogs. Our overall objective in this proposal is to investigate the role of Wnt/B-catenin signaling dysregulation in the etiology of failed vertebral bone formation in MPS VII and establish this pathway as a viable therapeutic target.