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Improved pharmacological chaperones for the treatment of neuronopathic Gaucher and Parkinson's disease
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Abstracts / Molecular Genetics and Metabolism 102 (2011) S3–S47
Improved pharmacological chaperones for the treatment of neuronopathic Gaucher and Parkinson's disease Sean Clark, Gary Lee, Robert Boyd, Sean Sullivan, Lee Pellegrino, Michelle Frascella, Richie Khanna, Nastry Brignol, Brandon Wustman, Philip Rybczynski, Elfrida Benjamin, Kenneth Valenzano, David J. Lockhart, Amicus Therapeutics, Cranbury, NJ, USA Parkinson's disease (PD) may share an etiological basis with Gaucher disease, as GBA1 mutations lead to Gaucher disease when homozygous, and are associated with increased risk for PD when hetero- or homozygous. Neuronopathic forms of Gaucher disease and PD also share the therapeutic challenge of targeting the central nervous system (CNS). Pharmacological chaperones (PC) are orally available, small molecules that represent an innovative approach to specifically increasing the activity of target enzymes. AT2101 is a PC developed to enhance the enzyme deficient in Gaucher disease, glucocerebrosidase. The accumulation of α-synuclein in the CNS is a hallmark of PD. We have successfully utilized AT2101 for proof-ofconcept studies in which administration of AT2101 prevented the accumulation of α-synuclein in the brain of two murine PD models that overexpress human α-synuclein. We reasoned that the CNS exposure and other properties of AT2101 could be further improved while maintaining a good safety profile. For instance, AT2101 inhibits targets other than GCase and has a relatively long lysosomal half-life. An assessment of nearly 200 analogs of AT2101 led to the identification of several new PCs with superior characteristics, including greater CNS penetration, increased potency for enhancement of enzyme activity, accelerated efflux from both tissues and lysosomes, and improved target specificity. These new PCs are currently under investigation in models of Parkinson's and neuronopathic Gaucher disease.
doi:10.1016/j.ymgme.2010.11.039
An open-label phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff variants) Joe Clarkea, Don Mahuranb, Swati Sathec, Edwin Kolodnyc, Brigitte Rigatb, Julian Raimanb, Michael Tropakb, aHospital for Sick Children, Toronto, Ontario, Canada, bResearch Institute, Hospital for Sick Children, Toronto, Canada, cDept of Neurology, New York University Medical Center, NY, USA Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ßhexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. In vitro studies have shown that many mutations in either the alpha- or betasubunit of Hex A can be partially rescued following the growth of patient cells in the presence of the drug, pyrimethamine. The present clinical trial was undertaken to assess the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of oral pyrimethamine 16 weeks. Treatment efficacy was evaluated by measurements of leukocyte Hex A activity. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Marked variations in the pharmacokinetics of the drug among the patients were noted.
Significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. Pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. doi:10.1016/j.ymgme.2010.11.040
Genotype and phenotype correspondence for Sanfilippo A syndrome Renee Cooksley, Chester B. Whitley, University of Minnesota, Minneapolis, MN, USA Background: Mucopolysaccharidosis type IIIA (MPS IIIA) also known, as Sanfilippo Syndrome Type A, is an autosomal recessive lysosomal storage disorder that results from a deficiency of an enzyme involved in the degradation of heparan sulphate. Hypothesis: Considerable variation in the severity of the clinical phenotypes has been noted. This variation is linked to the genotype of the patient. Material/methods: Mutational analysis has been performed to genotype patients with Sanfilippo Syndrome type A, in- order to show a correspondence between the genotype and the phenotype. The gene for heparan sulfate sulfamidase (chromosome 17q25.3 [Scott et al., 1995]) was sequenced using ABI's big dye terminator platform on an ABI-Avant. Results: Fourteen patients were genotyped with twelve different mutations being observed. Out of these twelve mutations, four novel mutations were observed (L12P, D32E, L59F, and M376R). These results are pooled with data from the literature Conclusions: Based on this study, we proposed that the neurodegenerative phenotype of Sanfilippo Syndrome type A, defined by the slope of IQ/age, maybe defined classic/severe (~15/1); where as rare affected individuals have more attenuated phenotypes (with IQ/age being less then 12/1). Speculations: Once a correspondence has been determined, a rating system could be established to differentiate between an “attenuated” and a “classic” form of this disorder. We predict that genotype analysis can be used to (1) offer a prognosis for young intervals with Sanfilippo syndrome. (2) Affected therapy would be predicted to reduce the slope of neurodegeneration. (3) This provides the rational for newborn screening when affected therapy becomes available.
doi:10.1016/j.ymgme.2010.11.041
Small molecule inhibitors of Glycosaminoglycan Biosynthesis as substrate optimization therapy for the Mucopolysaccharidoses Brett Crawford, Jillian Brown, Kelli Tolmie, Ellen Christie, Jeremy Hanson, Charles Glass, Sergio Duron, Shripad Bhagwat, Zacharon Pharmaceuticals, Inc., San Diego, CA, USA The Mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases caused by a deficiency in enzymes responsible for the degradation of glycosaminoglycans (GAGs). Despite progress in treating many of the peripheral symptoms, the central nervous system (CNS) aspect of the disease remains unaddressed. To address this unmet need, we are developing a small molecule CNS penetrant therapy for MPS I, II, and III that works by altering the synthesis of the GAG implicated in the CNS disease, heparan sulfate. Our therapeutic approach, Substrate Optimization Therapy (SOT) is based on selectively modifying the synthesis of heparan sulfate to render it more readily degraded despite the presence of specific enzyme deficiencies. In vitro data with cultured
Abstracts / Molecular Genetics and Metabolism 102 (2011) S3–S47
Improved pharmacological chaperones for the treatment of neuronopathic Gaucher and Parkinson's disease Sean Clark, Gary Lee, Robert Boyd, Sean Sullivan, Lee Pellegrino, Michelle Frascella, Richie Khanna, Nastry Brignol, Brandon Wustman, Philip Rybczynski, Elfrida Benjamin, Kenneth Valenzano, David J. Lockhart, Amicus Therapeutics, Cranbury, NJ, USA Parkinson's disease (PD) may share an etiological basis with Gaucher disease, as GBA1 mutations lead to Gaucher disease when homozygous, and are associated with increased risk for PD when hetero- or homozygous. Neuronopathic forms of Gaucher disease and PD also share the therapeutic challenge of targeting the central nervous system (CNS). Pharmacological chaperones (PC) are orally available, small molecules that represent an innovative approach to specifically increasing the activity of target enzymes. AT2101 is a PC developed to enhance the enzyme deficient in Gaucher disease, glucocerebrosidase. The accumulation of α-synuclein in the CNS is a hallmark of PD. We have successfully utilized AT2101 for proof-ofconcept studies in which administration of AT2101 prevented the accumulation of α-synuclein in the brain of two murine PD models that overexpress human α-synuclein. We reasoned that the CNS exposure and other properties of AT2101 could be further improved while maintaining a good safety profile. For instance, AT2101 inhibits targets other than GCase and has a relatively long lysosomal half-life. An assessment of nearly 200 analogs of AT2101 led to the identification of several new PCs with superior characteristics, including greater CNS penetration, increased potency for enhancement of enzyme activity, accelerated efflux from both tissues and lysosomes, and improved target specificity. These new PCs are currently under investigation in models of Parkinson's and neuronopathic Gaucher disease.
doi:10.1016/j.ymgme.2010.11.039
An open-label phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff variants) Joe Clarkea, Don Mahuranb, Swati Sathec, Edwin Kolodnyc, Brigitte Rigatb, Julian Raimanb, Michael Tropakb, aHospital for Sick Children, Toronto, Ontario, Canada, bResearch Institute, Hospital for Sick Children, Toronto, Canada, cDept of Neurology, New York University Medical Center, NY, USA Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ßhexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. In vitro studies have shown that many mutations in either the alpha- or betasubunit of Hex A can be partially rescued following the growth of patient cells in the presence of the drug, pyrimethamine. The present clinical trial was undertaken to assess the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of oral pyrimethamine 16 weeks. Treatment efficacy was evaluated by measurements of leukocyte Hex A activity. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Marked variations in the pharmacokinetics of the drug among the patients were noted.
Significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. Pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. doi:10.1016/j.ymgme.2010.11.040
Genotype and phenotype correspondence for Sanfilippo A syndrome Renee Cooksley, Chester B. Whitley, University of Minnesota, Minneapolis, MN, USA Background: Mucopolysaccharidosis type IIIA (MPS IIIA) also known, as Sanfilippo Syndrome Type A, is an autosomal recessive lysosomal storage disorder that results from a deficiency of an enzyme involved in the degradation of heparan sulphate. Hypothesis: Considerable variation in the severity of the clinical phenotypes has been noted. This variation is linked to the genotype of the patient. Material/methods: Mutational analysis has been performed to genotype patients with Sanfilippo Syndrome type A, in- order to show a correspondence between the genotype and the phenotype. The gene for heparan sulfate sulfamidase (chromosome 17q25.3 [Scott et al., 1995]) was sequenced using ABI's big dye terminator platform on an ABI-Avant. Results: Fourteen patients were genotyped with twelve different mutations being observed. Out of these twelve mutations, four novel mutations were observed (L12P, D32E, L59F, and M376R). These results are pooled with data from the literature Conclusions: Based on this study, we proposed that the neurodegenerative phenotype of Sanfilippo Syndrome type A, defined by the slope of IQ/age, maybe defined classic/severe (~15/1); where as rare affected individuals have more attenuated phenotypes (with IQ/age being less then 12/1). Speculations: Once a correspondence has been determined, a rating system could be established to differentiate between an “attenuated” and a “classic” form of this disorder. We predict that genotype analysis can be used to (1) offer a prognosis for young intervals with Sanfilippo syndrome. (2) Affected therapy would be predicted to reduce the slope of neurodegeneration. (3) This provides the rational for newborn screening when affected therapy becomes available.
doi:10.1016/j.ymgme.2010.11.041
Small molecule inhibitors of Glycosaminoglycan Biosynthesis as substrate optimization therapy for the Mucopolysaccharidoses Brett Crawford, Jillian Brown, Kelli Tolmie, Ellen Christie, Jeremy Hanson, Charles Glass, Sergio Duron, Shripad Bhagwat, Zacharon Pharmaceuticals, Inc., San Diego, CA, USA The Mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases caused by a deficiency in enzymes responsible for the degradation of glycosaminoglycans (GAGs). Despite progress in treating many of the peripheral symptoms, the central nervous system (CNS) aspect of the disease remains unaddressed. To address this unmet need, we are developing a small molecule CNS penetrant therapy for MPS I, II, and III that works by altering the synthesis of the GAG implicated in the CNS disease, heparan sulfate. Our therapeutic approach, Substrate Optimization Therapy (SOT) is based on selectively modifying the synthesis of heparan sulfate to render it more readily degraded despite the presence of specific enzyme deficiencies. In vitro data with cultured