The National MPS Society awarded $471,000 for research grants in 2010. The funding the Society provides has been and continues to be crucial as we move forward with our mission to find the cures.
We received 45 letters of intent from researchers around the world for the seven grants offered in 2010. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 14 researchers.
All new grant recipients were awarded $60,000 for the two year grant, with half of the total provided each year. We received $60,000 from the Caterina Marcus Foundation, www.caterinamarcusfoundation.org, to fund a general research grant and $52,000 from Insieme per Gabriel, an ML family foundation in Graglia, Italy, for an ML Partnership Grant. We are honored that both foundations selected the National MPS Society as partners to fund this very important research.
An additional $15,000 will support the work of Brains for Brain. The Society will fund $25,000 to support the Lysosomal Disease Networks NIH grant research goals. The funding is designed for the Neuroimaging Core, which will benefit the four MPS projects. The International MPS Network will announce a grant in September for treatment of CNS in MPS III. The Society has allocated $5,000 for that Partnership Grant.
Mark J. Osborn, PhD
University of Minnesota, Minneapolis, MN
Gene therapy for the central nervous system pathology of MPS I
The lysosome acts as the acidic stomach of the cell and contains multiple enzymes responsible for the breakdown of glycosaminoglycans that are normal constituents of the cell that must be turned over and recycled. A loss of a lysosomal enzyme results in accumulation ofglycosaminoglycans resulting in swelling of the lysosome and loss/altered function of the cell resulting in system wide pathology. MPS I (Hurler syndrome) is caused by a mutation to the IDUA gene causing a loss of the IDUA enzyme that acts as a critical enzyme in the breakdown of glycosaminoglycans. One of the most severely affected organs in patients with Hurler syndrome is the brain that shows widespread pathology resulting in severe mental retardation. The available treatment options for Hurler syndrome do not effectively correct the brain pathology therefore we have proposed to test the ability of a novel protein we have developed to reduce the brain pathology of this disease. Our protein is a hybrid comprised of transferrin and IDUA and is able to cross from the blood into the brain and therefore is able to be delivered in a minimally invasive fashion. We will test this protein by delivering a gene encoding it into MPS mice that have been engineered to mimic the human disease. Our pre-clinical testing will provide proof of concept for pursuing similar studies in humans.
Brett E. Crawford, Ph.D.
Zacharon Pharmaceuticals Inc., La Jolla CA,
Glycosaminoglycan inhibitors as substrate reduction therapies for MPS II
The proposed research project aims to produce a new drug for treating mucopolysaccharidosis (MPS). MPS occurs due to the toxic buildup of cellular carbohydrates (glycosaminoglycans) in cells which lead to serious symptoms ranging from physical deformity, cardiac, joint, andneurological dysfunction. Glycosaminoglycan buildup occurs due to mutations that inactivateenzymes that normally degrade these glycans. Through our previously supported research, we have identified compounds that can alter the synthesis of glycosaminoglycans so that they can becleared from patients with MPS. Our most advanced compounds have demonstrated efficacy in MPS models and are able to enter the central nervous system. These compounds represent a critical starting point for the development of a treatment for the neurological aspect of these diseases. Additionally, due to the mechanism of action (by targeting the biosynthesis of glycosaminoglycans), it is possible that this drug will be effective in multiple classes of MPS.The studies we propose here are aimed at identifying the most promising compound for future clinical development.
Elizabeth F. Neufeld, Ph.D.
UCLA. Los Angeles, CA
Making a minigene suitable for gene therapy for MPS IIIB
MPS IIIB is caused by mutations in the NAGLU gene, causing deficiency of the enzyme alpha-N-acetylglucosaminidase, storage of heparan sulfate and (in brain) of many additional substances. If proved safe, administration of the normal NAGLU gene would be the most effective therapy. Like many other lysosomal storage diseases, MPS IIIB is a candidate for gene therapy, requiring only that the normal gene be introduced into a small number of cells, which would manufacture the enzyme and provide it to neighboring cells, a process known as correction.The gene that is used in gene therapy is not the version found in nature, which is too large to administer to cells or animals. The therapeutic gene is the cDNA version, which is smaller. Ten years ago, we cloned NAGLU cDNA and were disappointed to find that the resulting alpha-Nacetylglucosaminidase was poorly corrective. Nevertheless, this cDNA has been used by four laboratories for gene therapy in MPS IIIB mice. Although all reported therapeutic results, two noted that the results were less than expected. Yet there are plans to use this only partially effective cDNA for clinical trials. Our hypothesis is that segments of DNA taken out of the native NAGLU gene may be important to make an enzyme that will be processed the normal way. This proposal is to make a minigene, which would yield a corrective enzyme and therefore be better suited for gene therapy.
Calogera M. Simonaro PhD., Associate Professor
Mount Sinai School of Medicine, New York, New York
A Novel Approach for the Growth & Expansion of Bone Marrow-Derived Mesenchymal Stem Cells in Mucopolysaccharidoses Type IV and Other Mucopolysaccharidoses
The overall goal of our research is to develop and evaluate new treatment approaches for two important organ systems in the mucopolysaccharidoses (MPS), the bones and joints. The current project is based on recent work showing that an enzyme, recombinant acid ceramidase (rAC), can be used to maintain and expand a unique population of stem cells from the bone marrow. Bone marrow transplantation (BMT) and related gene therapy procedures have been extensively evaluated in MPS patients and/or animal models, with varying degrees of success. While various factors have influenced this outcome, an important limitation is the very low frequency of stem cells within the bone marrow, leading to very low levels of transplanted cells at the disease sites. Direct injection of these cells into these sites helps, however even here the number of surviving cells is very small. Despite these limitations, clinical improvements have been observed, and there is a general agreement in the field that the approach is beneficial, but needs to be enhanced. In this project we will evaluate whether rAC can be used to improve the outcome of BMT, particularly in the bones and joints. Due to the unavailability of a suitable MPS IV animal model that mimics the severe bone and joint disease seen in patients, we will focus our efforts on the MPS VI rat. We will also study the effect of rAC on the growth and transplantation of cells obtained directly from normal and MPS cartilage. If successful, we believe that this approach could greatly improve the outcome of cell-based transplantation procedures in all of the MPS disorders, including MPS IV, and have general applicability to other genetic disorders as well.
Dr. Katrin Kollmann, PhD Partnership Grant with Insieme per Gabriele
University Medical Center Hamburg-Eppendorf , Hamburg, Germany
Skeletal abnormalities in mucolipidosis II alpha/beta Pathomechanisms and therapeutic strategies
Skeletal abnormalities are common symptoms in mucolipidosis II (ML II) and ML III patients leading to a decline in mobility, stiffness and chronic joint pain. In patients bone cells the transport of multiple lysosomal enzymes to lysosomes is altered impairing the function of bone-forming osteoblasts, bone-resorbing osteoclasts and of chondrocytes of the cartilage resulting in osteoporosis. In this study the expression of proteins and genes will be analyzed in cultured bone cells and chondrocytes of a novel ML II mouse model to understand the mechanisms of osteoporosis and to identify novel targets for therapeutical strategies in this disease. Furthermore, ML II knock-in mice will be treated with inhibitors of bone resorption to reduce the osteoporotic phenotype. These experimental approaches might be of relevance especially for ML III and related lysosomal storage diseases with skeletal abnormalities such as MPS VI.
Dr. Andrea Ballabio Caterina Marcus Foundation Grant
TIGEM (Telethon Institute of Genetics & Medicine)
Modulating lysosomal function to treat mucopolysaccharidoses
We recently discovered that a master gene controls the function and biogenesis of organelles called lysosomes, structures inside cells which breaks down materials into compounds which can be used or discarded by the cell, as needed. This gene, named TFEB, activates lysosomal genes, induces lysosomal biogenesis and increases the ability of cell to degrade complex molecules. In this grant, we plan to build on this discovery and test novel therapies in vivo for the treatment of Mucopolysaccharidosis (MPS). The possibility of achieving global control of lysosomal function, if successful, would represent a paradigm shift in biology and have enormous implications on the therapy of several lysosomal storage disorders, including MPS.
Dr. Alisdair B. Boraston, PhD
University of Victoria, Victoria, BC, Canada
Discovery and assessment of inhibitor-based chemical chaperones as potential
agents for the treatment of mucopolysaccharidosis IIIB.
The mucopolysaccharidoses are a group of devastating genetic diseases for which there are currently no cures or even effective treatments. Mucopolysaccharidosis IIIB (MPS IIIB), or Sanfilippo syndrome, is one of these diseases that usually results in death by early adulthood. Our ability to study the cause of MPS IIIB at the atomic level will allow us to develop new medicines to treat MPS IIIB and improve the lives of people suffering from this disease.