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Feasibility of quantifying behavior in early progressive MPS II
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
by 10%. Overall, patients also had an improved sense of well being with very few adverse side effects.
doi:10.1016/j.ymgme.2018.12.208
193 Antisense oligonucleotide treatment targeting glycogen synthase (GYS1) in a mouse model of Pompe disease Virginia Kimonisa, Lan Weissa, Michele Carrerb, Howard Yua, Nina Rabenc, Tamar Grossmanb, aUC Irvine, Orange, CA, United States, bIonis Pharmaceuticals, Carlsbad, CA, United States, cNational Institutes of Health, Bethesda, MD, United States. Pompe disease is a progressive myopathy resulting from the deficiency of acid α-glucosidase (GAA). The standard of care is ERT with recombinant human (rh) GAA. ERT works well in alleviating the cardiomyopathy however, many patients continue to have progressive muscle weakness from muscle glycogen accumulation produced by muscle glycogen synthase (GYS1). Previous studies have shown that inhibition of GYS1 reduced lysosomal glycogen. Knockdown of GYS1 mRNA by phosphorodiamidate morpholino oligonucleotide conjugated with a cell penetrating peptide however wasnephrotoxic. Antisense Oligonucleotides (ASO) technology has emerged as a powerful therapeutic alternative for the treatment of genetic disorders by targeting RNA. In order to impart specificity for the muscle variant of GYS1, we propose the use of ASO-mediated gene silencing through the RNaseH1 dependent degradation mechanism. Most recently therapy for spinal muscular atrophy has been successful using ASOs, and our hope is that ASO technology will be successful in Pompe disease. Over 150 ASOs were designed and screened in vitro to identify the most efficacious ASO for testing in wild type mice. The lead from the screen were validated in a dose response study and the top 10 ASOs were screened in vivo. The 2 ASOs (GYS1 ASO#1 and GYS1 ASO#2) showed the best tolerability and efficacy profile leading to knock down of GYS1 mRNA by approximately 50% of control. We have performed a pilot study of the efficacy of two GYS1 ASOs in Pompe mice as monotherapy and have reduced muscle GYS1 mRNA levels versus PBS and a mismatch ASO. ASO#2 resulted in weight loss of the mice. We will present the results of the study of the effect of the GYS1 ASOs on muscle glycogen, histology, GYS1 RNA and muscle function in Pompe mice. These preliminary studies provide proof of principle for a promising adjunct treatment for Pompe disease.
doi:10.1016/j.ymgme.2018.12.209
194 Feasibility of quantifying behavior in early progressive MPS II Kelly E. Kinga, Elsa G. Shapiroa, Chester B. Whitleya, Joseph Muenzerb, Julie B. Eisengarta, aUniversity of Minnesota, Minneapolis, MN, United States, bUniversity of North Carolina, Chapel Hill, NC, United States Hunter syndrome is a rare X-linked lysosomal disorder associated with progressive multisystem involvement. Ages of onset vary, as do disease course and phenotypic severity. The early progressive phenotype involves delayed developmental milestones with
S85
worsening intellectual impairment and regression. Disease progression creates dramatic neurobehavioral symptoms, including hyperactivity, inattention, behavior difficulties, sleep disturbance, and others. These behaviors are highly disruptive, distressing to families, and significantly impact quality of life. But these symptoms have been difficult to measure. Existing pediatric behavioral assessment tools do not capture the unique constellation of symptoms, nor variability of expression. To address this problem, we are developing a Hunter-specific caregiver rating scale of neurobehavioral symptoms. The goal is to create a valid, reliable tool that detects change in neurobehavioral profile, informing natural history and therapeutic response. A first step involves drafting a tool using methods of scale development for another MPS type with neurobehavioral impairment, the Sanfilippo Behavior Rating Scale. Item sets are informed by coded video recordings of: 1) semi-structured play in small groups of affected boys and 2) focus groups with caregivers literature review and review of existing tools. Inclusion criteria include: 1) confirmed diagnosis of early progressive Hunter syndrome 2) age 4 to 9 years 3) able to ambulate. Findings aligned with the literature’s descriptions of diverse symptoms, with considerable differences in presentation within-child, dependent upon internal and external factors (e.g., fatigue, hunger, novelty of a setting). Caregiver reports indicated a need for a behaviorally anchored scale that assesses frequency of symptoms and context rather than severity. Next steps will involve piloting the draft scale and soliciting caregiver feedback. Future directions include validating the measure in a larger multicenter study. Support: Shire pharmaceuticals, NIH U54NS065768, National MPS Society, UMN Center for Neurobehavioral Development
doi:10.1016/j.ymgme.2018.12.210
195 Safety and efficacy of VAL-1221, a novel fusion protein targeting cytoplasmic glycogen, in patients with late-onset Pompe disease Priya Kishnania, Robin Lachmannb, Tahseen Mozaffarc, Crista Waltersa, Laura Casea, Matt Applebyd, Vincenzo Librid, Manisha Kakc, Marie Wencelc, Hal Landye, aDuke University, Durham, NC, United States, bNational Hospital for Neurology and Neurosurgery, London, United Kingdom, cUniversity of California, Irvine, Orange, CA, United States, dUCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, United Kingdom, eValerion Therapeutics, LLC, Concord, MA, United States Disease progression in Pompe Disease, a lysosomal storage disorder, occurs despite enzyme replacement therapy ERT, and is characterized by cytoplasmic accumulation of glycogen, presumably due to rupture or seepage of glycogen from lysosomes, defects in autophagy and the targeting of conventional ERT only to the lysosome. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody utilizing the nucleoside transporter ENT-2 to gain access to the cytosol, and recombinant human acid alpha glucosidase (rhGAA), which enters lysosomes via mannose-6phosphate receptors (M6PRs). Thus, VAL-1221 targets both cytosolic and lysosomal glycogen. 30 mg of VAL-1221 contains 20 mg of rhGAA. We performed a 3-month Phase 1/2 repeat dose, doseescalation study of VAL-1221 with an rhGAA (Myozyme/Lumizyme) control to assess its safety and preliminary efficacy. 12 adults with late-onset Pompe disease (LOPD) treated with rhGAA for at least one year were randomized (1:3) to rhGAA (20 mg/kg qow) or to VAL-
by 10%. Overall, patients also had an improved sense of well being with very few adverse side effects.
doi:10.1016/j.ymgme.2018.12.208
193 Antisense oligonucleotide treatment targeting glycogen synthase (GYS1) in a mouse model of Pompe disease Virginia Kimonisa, Lan Weissa, Michele Carrerb, Howard Yua, Nina Rabenc, Tamar Grossmanb, aUC Irvine, Orange, CA, United States, bIonis Pharmaceuticals, Carlsbad, CA, United States, cNational Institutes of Health, Bethesda, MD, United States. Pompe disease is a progressive myopathy resulting from the deficiency of acid α-glucosidase (GAA). The standard of care is ERT with recombinant human (rh) GAA. ERT works well in alleviating the cardiomyopathy however, many patients continue to have progressive muscle weakness from muscle glycogen accumulation produced by muscle glycogen synthase (GYS1). Previous studies have shown that inhibition of GYS1 reduced lysosomal glycogen. Knockdown of GYS1 mRNA by phosphorodiamidate morpholino oligonucleotide conjugated with a cell penetrating peptide however wasnephrotoxic. Antisense Oligonucleotides (ASO) technology has emerged as a powerful therapeutic alternative for the treatment of genetic disorders by targeting RNA. In order to impart specificity for the muscle variant of GYS1, we propose the use of ASO-mediated gene silencing through the RNaseH1 dependent degradation mechanism. Most recently therapy for spinal muscular atrophy has been successful using ASOs, and our hope is that ASO technology will be successful in Pompe disease. Over 150 ASOs were designed and screened in vitro to identify the most efficacious ASO for testing in wild type mice. The lead from the screen were validated in a dose response study and the top 10 ASOs were screened in vivo. The 2 ASOs (GYS1 ASO#1 and GYS1 ASO#2) showed the best tolerability and efficacy profile leading to knock down of GYS1 mRNA by approximately 50% of control. We have performed a pilot study of the efficacy of two GYS1 ASOs in Pompe mice as monotherapy and have reduced muscle GYS1 mRNA levels versus PBS and a mismatch ASO. ASO#2 resulted in weight loss of the mice. We will present the results of the study of the effect of the GYS1 ASOs on muscle glycogen, histology, GYS1 RNA and muscle function in Pompe mice. These preliminary studies provide proof of principle for a promising adjunct treatment for Pompe disease.
doi:10.1016/j.ymgme.2018.12.209
194 Feasibility of quantifying behavior in early progressive MPS II Kelly E. Kinga, Elsa G. Shapiroa, Chester B. Whitleya, Joseph Muenzerb, Julie B. Eisengarta, aUniversity of Minnesota, Minneapolis, MN, United States, bUniversity of North Carolina, Chapel Hill, NC, United States Hunter syndrome is a rare X-linked lysosomal disorder associated with progressive multisystem involvement. Ages of onset vary, as do disease course and phenotypic severity. The early progressive phenotype involves delayed developmental milestones with
S85
worsening intellectual impairment and regression. Disease progression creates dramatic neurobehavioral symptoms, including hyperactivity, inattention, behavior difficulties, sleep disturbance, and others. These behaviors are highly disruptive, distressing to families, and significantly impact quality of life. But these symptoms have been difficult to measure. Existing pediatric behavioral assessment tools do not capture the unique constellation of symptoms, nor variability of expression. To address this problem, we are developing a Hunter-specific caregiver rating scale of neurobehavioral symptoms. The goal is to create a valid, reliable tool that detects change in neurobehavioral profile, informing natural history and therapeutic response. A first step involves drafting a tool using methods of scale development for another MPS type with neurobehavioral impairment, the Sanfilippo Behavior Rating Scale. Item sets are informed by coded video recordings of: 1) semi-structured play in small groups of affected boys and 2) focus groups with caregivers literature review and review of existing tools. Inclusion criteria include: 1) confirmed diagnosis of early progressive Hunter syndrome 2) age 4 to 9 years 3) able to ambulate. Findings aligned with the literature’s descriptions of diverse symptoms, with considerable differences in presentation within-child, dependent upon internal and external factors (e.g., fatigue, hunger, novelty of a setting). Caregiver reports indicated a need for a behaviorally anchored scale that assesses frequency of symptoms and context rather than severity. Next steps will involve piloting the draft scale and soliciting caregiver feedback. Future directions include validating the measure in a larger multicenter study. Support: Shire pharmaceuticals, NIH U54NS065768, National MPS Society, UMN Center for Neurobehavioral Development
doi:10.1016/j.ymgme.2018.12.210
195 Safety and efficacy of VAL-1221, a novel fusion protein targeting cytoplasmic glycogen, in patients with late-onset Pompe disease Priya Kishnania, Robin Lachmannb, Tahseen Mozaffarc, Crista Waltersa, Laura Casea, Matt Applebyd, Vincenzo Librid, Manisha Kakc, Marie Wencelc, Hal Landye, aDuke University, Durham, NC, United States, bNational Hospital for Neurology and Neurosurgery, London, United Kingdom, cUniversity of California, Irvine, Orange, CA, United States, dUCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, United Kingdom, eValerion Therapeutics, LLC, Concord, MA, United States Disease progression in Pompe Disease, a lysosomal storage disorder, occurs despite enzyme replacement therapy ERT, and is characterized by cytoplasmic accumulation of glycogen, presumably due to rupture or seepage of glycogen from lysosomes, defects in autophagy and the targeting of conventional ERT only to the lysosome. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody utilizing the nucleoside transporter ENT-2 to gain access to the cytosol, and recombinant human acid alpha glucosidase (rhGAA), which enters lysosomes via mannose-6phosphate receptors (M6PRs). Thus, VAL-1221 targets both cytosolic and lysosomal glycogen. 30 mg of VAL-1221 contains 20 mg of rhGAA. We performed a 3-month Phase 1/2 repeat dose, doseescalation study of VAL-1221 with an rhGAA (Myozyme/Lumizyme) control to assess its safety and preliminary efficacy. 12 adults with late-onset Pompe disease (LOPD) treated with rhGAA for at least one year were randomized (1:3) to rhGAA (20 mg/kg qow) or to VAL-