The National MPS Society allocated $429,500 in grant funding for 2015 which includes the second year funding for grants awarded in 2014. The funding the Society provides has been and continues to be critical as we move forward with our mission to find the cures. We received 30 letters of intent from researchers around the world for the General, MPS I, MPS III and MPS IVA grants. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from ten researchers.
The Board of Directors allocated $94,000 for the first Fundraiser Directed Research grant. The family who raised these funds requested that they be allocated to Dr. Brian Bigger at the University of Manchester in the UK for his MPS II research, “Improving stem cell therapy for severe MPS II.”
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. Dr. Michael Gelb at the University of Washington is conducting a pilot study for MPS II newborn screening, and the Society awarded Dr. Gelb $34,000 for this study. An additional $16,000 was offered for an ML grant in partnership with ISMRD (International Society for Mannosidosis and Related Diseases). The Society also provided $4,500 for post-doctoral fellows to attend the Lysosomal Disease Gordon Conference.
Dr. Carmine Settembre
Telethon Institute of Genetics and Medicine of Fondazione Telethon
“Targeting mTORCI and autophagy pathways to rescue the skeletal phenotype in MPS mouse models”
The mechanism by which lysosomal storage in bone cells affects skeletal development is still unknown. Current therapies for MPS showed very little efficacy for the treatment of this aspect of the disease. Our lab is focused on the identification of the molecular mechanisms accounting for the skeletal phenotype in MPS, with the final goal to identify a novel therapeutic strategy for the treatment of this debilitating feature. In this grant application we propose to modulate in vivo the activity of two cellular metabolic pathways, which we found to be altered in MPS cartilage cells, as an attempt to cure the skeletal phenotype in MPS patients.
Dr. Allison R. Kermode, Professor
Simon Fraser University
Burnaby, BC Canada
“Validation of small molecule therapeutic leads for treatment of MPS I disease”
Mucopolysaccharidosis I (MPS I) is a serious genetic disease that leads to early death. In this disease, there is a single enzyme that is missing or deficient, an enzyme that resides in human cells in special organelles (lysosomes). Enzyme replacement therapy is the conventional treatment but the associated drug is very costly (up to one million dollars per patient per year). Furthermore the treatment is not effective for disease processes in the brain and skeleton, partly because the supplied enzyme cannot gain access to these tissues. Another type of therapy is enzyme enhancement therapy. This uses a small molecule that assists the otherwise defective lysosomal enzyme to adopt the correct shape. The result is enhanced enzymatic activity – the enzyme achieves its correctly folded conformation and can now transit inside the human cell to arrive at its normal locale where it can function, the lysosome. We recently identified a drug candidate that would be less costly, allow for oral delivery, and has well-known properties. We will evaluate this molecule for its therapeutic value in the treatment of MPS I disease. We will further determine how this small molecule and related compounds work to rescue defective enzymes and thus act as therapeutics.
Dr. Kim Hemsley
Lysosomal Diseases Research Unit
Adelaide, SA, Australia
“AAV2/8 medicated expression of modified sulphamidase: Liver targeting for improved secretion and brain deliver. Pre-clinical study in the Huntaway dog”
This is a pre-clinical trial of a new gene therapy approach for Sam Filippo syndrome type A. The therapy treats brain disease in mice with 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 important to determine 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 injection 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 normalizes 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 MPS IIIA. A modified form of this treatment approach could also be used for other brain diseases.
Dr. Ainslie Derrick-Roberts
Genetics and Molecular Pathology
North Adelaide, SA, Australia
“Creating new tools for understanding skeletal disease in MPS IVA”
Animal models and cell-based models have proven invaluable in furthering our understanding of the natural progression of MPS disease and in assessing the efficacy of various therapeutic approaches. Studies in our laboratory using a feline model of MPS VI directly led to the translation of enzyme replacement therapy into clinical practice for MPS VI and the related MPS types I and II. Unfortunately, no comparable system exists for MPS IVA. Our understanding of disease progression as a result is poor and hampers our ability to design and evaluate therapy that specifically targets MPS IVA sites of pathology in particular tissues within the joint. In this study a mouse model of MPS IVA and a cell-based model of MPS IVA will be developed and then used to evaluate a gene therapy approach to correcting disease and to determine how key developmental pathways are regulated in MPS IVA in particular the formation of cartilage cells.