Substrate Optimization Therapy: A Novel Therapy for Mucopolysaccharidosis

DESCRIPTION (provided by applicant): Project Summary The studies proposed in this application will test the feasibility of treating mucopolysaccharidosis (MPS) through a novel therapeutic approach called Substrate Optimization Therapy (SOT). MPS is a family of lysosomal storage diseases caused by mutations in the enzymes that normally degrade glycosaminoglycans (GAGs). Because of deficiencies in the mutated enzymes, GAGs build up to toxic levels causing a wide range of symptoms including severe mental retardation, cardiac dysfunction, and early death. Current therapies attempt to compensate for the deficiencies by IV infusion of specific recombinant enzymes, Enzyme Replacement Therapy (ERT). Patients, especially those only mildly affected, do receive some benefit from ERT, however the benefit is limited primary because of minimal penetration of infused enzymes in tissues with restricted blood flow such as joints (synovial capsule), heart valve (cartilage), and brain (blood brain barrier). Further, many patients rapidly develop blocking antibody responses to ERT, an effect that is most pronounced in those patients that are most severely affected. Substrate Optimization Therapy is novel because it uses the first ever small molecule GAG biosynthesis inhibitors to subtlety shape the fine structural composition of GAGs in patients, enabling the GAGs to be degraded despite the pathogenic enzyme deficiency. The small molecule approach is superior because it can penetrate the relevant tissues including the central nervous system, heart valve, bone, and joints plus it avoids issues of antibody inhibition in those patients most in need of treatment. Also, due to the underlying biology and disease pathogenesis, this approach will treat both MPS I and MPS II with a single therapeutic agent. Through the studies proposed in this application, we will identify the best small molecule SOT agents for a proof of concept efficacy study in the mouse model of MPS II. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to test the feasibility of a novel therapeutic approach to treating mucopolysaccharidosis II (MPS II). MPS II is a rare genetic disease that is currently only partially managed through weekly intravenous injections. Through this grant we aim to identify compounds that are the crucial starting point for the development of the first orally available CNS penetrant therapy for this devastating disease.