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Patent
Zacharon Pharmaceuticals Inc. | Date: 2012-07-16

Provided herein are methods of diagnosing or monitoring the treatment of abnormal glycan accumulation or a disorder associated with abnormal glycan accumulation.


Patent
Zacharon Pharmaceuticals Inc. | Date: 2010-12-28

Provided herein are chondroitin sulfate inhibitors, including modulators of glycosylation, and/or sulfation of galactose or N-acetyl galactosamine glycosaminoglycans.


Patent
Zacharon Pharmaceuticals Inc. | Date: 2010-03-29

Provided herein are ganglioside synthesis inhibitors, including modulators of ganglioside glycosylation.


Patent
Zacharon Pharmaceuticals Inc. | Date: 2012-09-27

Provided herein are methods of diagnosing or monitoring the treatment of abnormal glycan accumulation or a disorder associated with abnormal glycan accumulation.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 339.51K | Year: 2010

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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 342.90K | Year: 2011

DESCRIPTION (provided by applicant): Project Summary Using a novel high-throughput screening approach, we have recently identified the first selective small molecule inhibitors of the biosynthesis of gangliosides. The proposed funding will enable important preclinical development activities required to advance these promising compounds as a novel therapy for the GM2 gangliosidoses. GM2 gangliosidosis is a family of genetic diseases including Tay-Sachs, Sandhoff, and the AB variant that are causedby mutations in subunits of the enzyme complex required to degrade gangliosides. Due to the lysosomal enzyme deficiency, gangliosides build up to toxic levels leading to severe neurological decline and death. The ganglioside biosynthetic inhibitors would be expected to alleviate disease severity through a substrate reduction mechanism by selectively restricting the ganglioside flux through the compromised lysosomal degradative system. We will test if these compounds can reduce lysosomal gangliosideaccumulation in fibroblasts from patients with GM2 gangliosidosis. Active scaffolds will then be tested for important physiochemical, pharmacological and medicinal chemistry properties to identify the most promising scaffolds for further development. When completed, these studies will lay the foundation for additional preclinical development of the first therapy for these devastating diseases. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to complete important early-stageproduct development activities for a new therapy to treat two related and devastating diseases: Tay-Sachs and Sandhoff diseases. These genetically-induced diseases are present from birth and lead to severe neurological damage and premature death. Noeffective treatments exist for these conditions. As a result, the proposed research has the potential to enable the first effective treatment for two devastating, childhood diseases associated with significant morbidity and mortality.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 335.74K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a biomarker capable of definitively diagnosing and monitoring response to therapy in patients with Mucopolysaccharidosis (MPS) I, II and VI. These diseases are rare genetic conditions each caused by unique deficiencies in the lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs). The resulting lysosomal accumulation of GAG fragments leads to severe physical, developmental, and neurological symptoms with dramatic heterogeneity between different patients. Since lysosomal GAG accumulation is the primary cellular event triggered by the lysosomal enzyme deficiency, the measurement of GAGs is an ideal biomarker of the disease. Unfortunately, prior attempts to quantify GAG accumulation have been unsuccessful due to the extremely variable polymer length and sulfation and significant background from non-pathogenic GAGs that are normally present in biological samples. The Sensi- Pro method solves this problem using an innovative approach to quantify the unique GAG structures that arise due to the specific lysosomal defect. Because each MPS disorder is deficient in a distinct lysosomal degradative enzyme, the Sensi-Pro biomarkers are discrete for each MPS disorder and are not found in unaffected people. The Sensi-Pro assay has demonstrated the ability to quickly and accurately differentiate the various MPS disorders in addition to the ability to monitor individual patient responses to the FDA approved therapies. This proposal aims to develop the Sensi-Pro assay further for clinical use for the differential diagnosis and measurement of response to therapy in MPS I, II and VI. This will be accomplished through a series of studies in collaboration with ARUP Laboratories designedto establish the standards for the MPS I, II, and VI biomarkers, multiplex the assay, and validate the assay in a CLIA compliant environment. With the multiplexed assay established, it will be tested for the ability to differentiate between MPS disordersand detect a response to therapy in samples from a clinical trial for MPS I. Upon successful completion, the assay will be commercialized by ARUP Laboratories as a clinical assay for the definitive identification of MPS patients and optimization of treatment protocols. PUBLIC HEALTH RELEVANCE: This research is designed to develop a novel biomarker for the definitive diagnosis and clinical management of patients with Mucopolysaccharidosis I, II, and VI. These diseases are rare genetic conditions caused by defects in the cellular systems required to degrade carbohydrates. The successful conclusion of this research will provide a critical diagnostic tool enabling the identification of affected patients, selection of appropriate therapy, and optimization of treatment strategies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 296.24K | Year: 2012

DESCRIPTION (provided by applicant): The objective of this Phase I SBIR proposal is to develop a central nervous system penetrant (CNS) small molecule therapy for Metachromatic Leukodystrophy (MLD). We will accomplish this by developing a cellular model ofMLD to screen compound libraries in order to identify small molecule screening hits suitable for lead optimization to develop drugs for the treatment of this devastating disease. MLD is a rare genetic condition found in 1 in 40,000 births that is caused by a deficiency in the lysosomal arylsulfatase A (ASA) or saposin B (SAPB) [1, 2]. The lack of ASA activity leads to widespread accumulation of 3-O sulfated glycolipids in the lysosomes of cells. The accumulation of sulfated glycolipids in oligodendrocytesand neurons in the CNS leads to the profound neurological deterioration and ultimately death. In this proposal, we aim to change this situation by developing a model of MLD based on cells from patients with MLD. This assay will enable the high throughput screening of compound libraries in order to identify novel treatments for this destructive disease. To accomplish this, we propose to develop rapid analytical method for the quantitation of the primary 3-O sulfated glycolipid (sulfatide) that accumulates incultured human MLD cells. This assay will be used to screen compound libraries for inhibitors of lysosomal sulfatide storage. Finally, the hits will be prioritized based on their mechanisms, potency, ADME, and PK properties. Upon successful completion ofthis proposal, we will have identified the hit compounds that can serve as the starting point for the discovery and development of a novel CNS penetrant therapy for MLD. PUBLIC HEALTH RELEVANCE: This research is designed to identify a treatmentfor Metachromatic Leukodystrophy, a genetic condition that causes severe neurological disease. There are currently no effective therapeutic options for this life threatening disease. If successful, this research could lead to a therapy for Metachromatic Leukodystrophy.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2011

DESCRIPTION (provided by applicant): Project Summary The studies proposed in this application are aimed at progressing an innovative approach to treating mucopolysaccharidoses (MPS) toward clinical trials. 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 developblocking antibody responses to ERT, an effect that is most pronounced in those patients that are most severely affected. Our therapeutic approach (Substrate Optimization Therapy, SOT) 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 MPS I, II, andIII with a single therapeutic agent. Through the studies proposed in this application, we will complete the preclinical and IND enabling studies required to initiate a Phase I clinical trial. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to develop a new therapy for treating mucopolysaccharidosis (MPS). MPS is a collection of rare childhood genetic diseases that are currently only partially managed through weekly intravenous injections that do not treat the neurological deficits arising from the diseases. Through this grant we aim to develop the first therapy to treat all symptoms including the devastating neurological deficits of these diseases.


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