The National MPS Society awarded $421,500 in grant funding for 2011. 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 33 letters of intent from researchers around the world for the five grants offered in 2011. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 13 researchers.
All grant recipients were awarded $70,000 for the two year grant, with half of the total provided each year. 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 Society also provides funding for post-doctoral fellows to attend scientific meetings, such as the American Society of Gene and Cell Therapy and the Gordon Conference on Lysosomal Diseases.
MPS II Grant
Vito Ferro, Small molecule chaperons for ERT for MPS II
MPS II is caused by defects in an enzyme called iduronate-2-sulfatase. L Many of these defects result in degradation of the enzyme in cells before it has had a chance to carry out its normal function, thus producing clinical symptoms. MPS II patients may be treated with enzyme replacement therapy in which a synthetic, fully functional enzyme is administered by injection. Unfortunately, the replacement enzyme cannot cross the blood-brain barrier and thus cannot relieve the neurological symptoms associated with severe cases of MPS II. The aims of this project are to develop small molecules for the treatment of MPS II, which unlike enzymes, are capable of crossing the blood-brain barrier and thus may offer relief of neurological symptoms. The small molecules are designed to act as chaperones to protect the defective enzyme from degradation and restore enzyme activity to sufficient levels to relieve symptoms. This approach has shown great promise in other lysosomal storage diseases but has yet to be extended to MPS II. This project will address that situation.
MPS III Grant
Patricia Dickson, Choriod plexus-directed gene therapy as a source of intraventricular NAGLU-IGF2 for MPS IIIB
Animal models of MPS types I, II and IIIA can be treated by providing recombinant enzyme into the fluid surrounding the brain (cerebrospinal fluid). The application of this treatment of IIIB has been hampered by the inability of the missing enzyme, alpha-?-acetylglucosaminidase (NAGLU), to enter cells efficiently. We have created NAGLU tagged with insulin-like growth factor 2 (IGF2) which enters cells effectively using the mannose 6-phosphate receptor. Here, we will deliver NAGLU-IGF2 to the cerebrospinal fluid by using gene therapy in animal models. We will target the part of the brain that makes cerebrospinal fluid (the choroid plexus), to determine whether this will provide a source of NAGLU-IGF2 for the brain. This study will provide proof-of-principle for choroid-plexus directed gene therapy with NAGLU-IGF2 as a potential therapy for MPS III IIIB, to determine whether this approach can deliver enzyme using cerebrospinal fluid without the need for repeated injections.
Alberto Auricchio, Gene therapy of MPS VI
Enzyme replacement therapy for MPS VI requires weekly administrations of costly enzyme and has a poor outcome on some of the disease characteristics including bone and cartilage abnormalities. We have recently shown that a single systemic delivery of an adeno-associated viral vector (AAV) encoding the correct copy of the enzyme missing in MPSVI results in: i.sustained expression of the enzyme from liver of MPS VI cats transduced by AAV; ii.significant amelioration of the disease phenotype (including bone and cartilage) in this large model of the disease.
Based on these promising results we are planning a clinical trial to test the safety and efficacy of our approach in MPS VI patients. Towards this goal we propose to:
complete some of the pre-clinical data required for further clinical development
develop bioengineered enzyme molecules with improved secretion or bone uptake which may increase the efficacy of gene therapy and lower the vector doses used in patients.
We believe these data will be instrumental to rapidly move gene therapy for MPS VI from bench to bedside thus overcoming some of the limitations of current therapies. In addition, the results from these studies may improve the cures for other MPS.
Adriana Montano, Role of inflammation in pathogenesis of MPS IVA
Morquio A disease is characterized with the build-up of two specific sugars (chondroitin-6- sulfate and keratan sulfate) in all the body cells, particularly in skeletal tissue. Effects of this build-up on the immune system and the consequences on the cartilage destruction and alterations of bone metabolism in Morquio A disease have not been investigated yet. We will clarify the role of immune system in the pathogenesis of Morquio A disease. We will characterize the immune profile of Morquio A mouse bone and cartilage cells and tissues, as well as Morquio A human cartilage cells. The outcome of this research will enable us to develop better approaches for treatment strategies to stop cartilage degeneration not only in Morquio A but also in other MPS.
Richard Steet, Blockade of cathepsin activity and TGF-beta signaling as a therapeutic approach for LSDs
Understanding the molecular events that cause disease symptoms is an important step in the development of new therapies for many inherited disorders, especially in cases where replacement of the defective gene or enzyme is difficult. In earlier studies, we showed that the cartilage defects in a zebrafish model for ML-II are associated with increased activity of protein-degrading enzymes called cathepsins and excessive TGF-beta signaling. Our most recent work now demonstrates that reducing the activity of one of these enzymes, cathepsin K, results in correction of the cartilage defects in ML-II zebrafish embryos. Using known drugs, we now propose to block the activity of two other cathepsin proteases and to reduce excessive TGF-beta signaling to determine how these molecules impact the onset and progression of disease phenotypes such as impaired development of cartilage and heart valves. Since elevated cathepsin activity is a common feature of many MPS disorders, we believe our results on ML-II will increase our understanding of the disease mechanisms associated with other lysosomal diseases.