All grant recipients were awarded $80,000 for the two year grant, with half of the total provided each year. Dr. Cosma received the MPS II grant, Drs. Esko and Fraldi received the MPS III grants, and Drs. Ponder and Simonaro received the general MPS research grants.
An additional $7,000 for mucolipidosis research will be provided as a partnership grant to ISMRD (International Society of Mannosidosis and Related Diseases). In support of the Lysosomal Disease Networks NIH grant research goals, the Society will fund $25,000 for the Neuroimaging Core which will benefit the four MPS projects.
Dr. Maria Pia Cosma
TIGEM, Naples, Italy
AAV2/5CMV-IDS therapy in MPSII mice: correction of CNS defects through IDS
delivery across the blood-brain barrier.
Children affected by mucopolysaccharidosis type II (MPSII; Hunter syndrome) lack the activity of the enzyme iduronate 2-sulfatase (IDS). They accumulate compounds in their body that gradually kill their cells and damage all of their visceral organs. A gene therapy approach was initiated to treat this central nervous system (CNS) disease in a mouse model of MPSII. Affected pups were injected with viral particles that targeted all of the visceral tissues. High levels of active IDS were produced, secreted into the plasma and also taken up by the brain. This approach gave important results, as the mice were cured of their visceral organ defects, and surprisingly, they also showed amelioration of the CNS phenotype. We now plan to extend this approach to adult and juvenile MPSII mice and to more specifically study how the IDS enzyme reaches the brain, in terms of its crossing of the blood-brain barrier, which was thought not to be permeable to high molecular weight proteins, such as the IDS. We plan to carry out these studies with a variety of different approaches. If successful, our studies should allow us to set up more efficient treatments for the cure of the CNS phenotype of patients with Hunter syndrome.
Dr. Jeffrey Esko
University of California, San Diego, CA
Substrate reduction strategy for MPS IIIA
Mucopolysaccharidoses (MPS) are inherited metabolic disorders in which cellular polysaccharides (glycosaminoglycans) can no longer be degraded, causing aberrant storage of partially degraded material in lysosomes. Children born with these diseases exhibit developmental abnormalities, organ failure and mental retardation, defects that often result in death within the first few decades of life. A subset of MPS diseases result from enzyme deficiencies required by cells to degrade a class of glycosaminoglycans known as heparan sulfate. This research proposal will test if altering heparan sulfate biosynthesis is an effective method of preventing its accumulation in one of these diseases, specifically MPSIIIA. The approach consists of genetically disrupting heparan sulfate biosynthesis in MPSIIIA patient cell lines and mouse models. Its efficacy will be assayed by reduction of lysosomal storage and restoration of normal cellular turnover of glycosaminoglycans. Positive results would justify and encourage the development of small molecule inhibitors of heparan sulfate biosynthesis as a way to accomplish substrate reduction therapy in patients. The major advantage of substrate reduction is that these agents might access the brain where glycosaminoglycan storage is highly detrimental and existing therapies appear ineffective
Dr. Alessandro Fraldi
TIGEM, Naples, Italy
Developing a systemic AAV-mediated gene therapy to cross the blood-brain barrier and treat the brain pathology in MPS IIIA
Mucopolysaccharidosis type IIIA (MPS-IIIA) is an inherited disease caused by the deficiency of sulfamidase (SGSH), a gene that encode an enzyme needed for the degradation of a large macromolecule called heparan sulfate. As consequence, such substrate accumulates in the cells and tissues of the affected patients causing cell damage. The central nervous system is the predominant target of damage and in fact, the MPS-IIIA patients experience severe mental retardation and neuropathological decline that ultimately leads to death. Gene therapy is a therapeutic option for several inherited diseases. The aim of gene therapy is to substitute the defective gene with a functional one. Often a modified not-pathogenic virus is used as vehicle to transport the gene in the affected tissues. In this study we will test the efficacy of a therapeutic approach based on the delivery, via intravenous injection, of an adeno-associated virus (AAV) bearing a functional SGSH. The AAV have a tropism for the liver, so that upon injection the virus will reach the liver that consequently will produce the functional SGSH. The functional SGSH will be then secreted from the liver and will enter into the brain throughout the blood torrent. Importantly, the SGSH will be opportunely modified to be secreted more efficiently from the liver and to make it able to efficiently pass the blood-brain barrier and transduce the brain.
Dr. Katherine Ponder
Washington University, St. Louis, MO
The role of cathepsin K in cardiac valve disease in MPS
Mucopolysaccharidosis (MPS) is due to a genetic deficiency in the activity of an enzyme that degrades glycosaminoglycans. One of the serious manifestations of MPS is the development of heart disease, which can result in reduced delivery of oxygenated blood to the body and require surgery to replace the valve. This can involve thickened heart valves that block the flow of blood into the heart. Heart valves can also be leaky, which allows blood to flow in the wrong direction. The goal of this project is to understand what causes heart valves problems, and to identify a therapy to prevent these heart valve abnormalities from developing. Collagen is the major protein that provides strength to the heart valves. We have found that the amount of collagen is markedly reduced in heart valves of MPS I and MPS VII dogs, and propose that this is what weakens the valve. We hypothesize that reduced amounts of collagen are due to abnormally high levels of an enzyme that can degrade collagen, cathepsin K. It that is the case, it might be possible to prevent heart valve disease with inhibitors of cathepsin K that are currently being used to treat osteoporosis. This project may identify a drug to prevent the development of heart valve disease in MPS.
Dr. Calogera Simonaro
Mount Sinai School of Medicine, New York, NY
Novel anti-inflammatory therapies for the mucopolysaccharidoses
Enzyme replacement therapy (ERT) is currently available for three MPS diseases, although the effects of this therapy on bone and cartilage are very limited. Thus, new treatment approaches are clearly needed, alone or as adjuncts to ERT. Our research will use animal models to explore such new therapies. In particular, we will comprehensively evaluate the bones and joints of MPS VI animals treated with the FDA-approved anti-inflammatory drug, Remicade. This drug targets the inflammatory pathway we have found to be activated in MPS patients (TLR4). Our results to date have shown that Remicade can substantially reverse or prevent inflammation in MPS VI rats, and we now plan to comprehensively evaluate the bones and joints in animals treated with Remicade alone or in conjunction with ERT (Naglazyme). Since Remicade is currently FDA-approved for the treatment of arthritis and other inflammatory diseases, we are hopeful that completion of these animal studies will lead to clinical trials and approval for MPS patients. We will also complete the analysis of an important proof of principle experiment in which the TLR4 inflammatory pathway is inactivated in MPS VII mice. These results will provide the basis for the continued development of anti-inflammatory treatment strategies for MPS VI and other MPS disorders, and identify new molecular targets for drug therapy.