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Intravenous infusion of iPSC-derived neural progenitors expressing GCase ameliorates alpha-synuclein aggregates in a mouse model of Gaucher disease
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Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
Medical Center, Mainz, Germany, fNeuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice (CHU), Nice, France, gKU Leuven (Catholic University of Leuven) Department of Neurosciences, VIB - Center for Brain & Disease Research, University Hospitals Leuven - Department of Neurology, Leuven, Belgium, hCopenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, iSanofi Genzyme, Chilly-Mazarin, France, jSanofi Genzyme, Cambridge, MA, United States, kFriedrichBaur-Institut, Department of Neurology Klinikum München, München, Germany; 1Current affiliation: Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, , Cincinnati, OH, United States. Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat avalglucosidase alfa dosing (5, 10, or 20 mg/kg qow) for 6 months were evaluated in NEO1 (NCT01898364) in late-onset Pompe disease patients either treatment-naïve (Naïve) or having received alglucosidase alfa for ≥9 months (Switch). In NEO-EXT (NCT02032524), an ongoing NEO1 extension, long-term safety and pharmacokinetics of repeat avalglucosidase alfa dosing will be monitored over 6 years. Interim safety results after 4.5 years of NEO-EXT are reported here. Mean ages at NEO1 enrollment were: Naïve: 44.8 (SD:20.3, range:20-78) years and Switch: 46.7 (SD:14.1, range:21-68) years. Of the 24 NEO1 participants, 19 entered NEO-EXT (8/10 Naïve 11/14 Switch) 17 are currently participating (7/8 Naïve 10/11 Switch) 2 participants discontinued NEO-EXT (personal reasons). During 2016, all NEOEXT participants switched to avalglucosidase alfa 20 mg/kg qow. By May 2018, total infusions reached 731 (Naïve) and 1174 (Switch) mean infusions were Naïve: 73 (SD:43, range:9-113) and Switch: 84 (SD:40, range:8-118). Mean avalglucosidase alfa exposure duration reached 1025 (SD:611, range:109-1572) days for Naïve and 1179 (SD:570, range:102-1658) days for Switch participants. Treatmentemergent adverse events (AEs) were generally mild across doses. Most frequently reported treatment-related AEs were nausea, fatigue, and headache (3 participants each) and dizziness, dyspnea, erythema, myalgia, muscle spasms, and rash (2 participants each) and are unchanged since the last safety update (WORLDSymposium™ 2018). One Switch participant discontinued NEO1 for a study drug-related serious AE (respiratory distress/chest discomfort) no deaths/life-threatening serious AEs have occurred. Anti-avalglucosidase IgG/IgM antibodies developed in 9/10 Switch (median titer:1600, range:200-51,200) and 9/14 Naïve (median titer:400, range:50-12,800) participants. No patient developed IgE antibodies or tested positive for enzyme activity inhibition. In NEOEXT, the avalglucosidase alfa safety profile is consistent with the initial 6 months’ treatment during NEO1, with no additional participants developing anti-avalglucosidase alfa IgG/IgM antibodies or new allergic reactions. Funding: Sanofi Genzyme.
doi:10.1016/j.ymgme.2018.12.294
279 Intravenous infusion of iPSC-derived neural progenitors expressing GCase ameliorates alpha-synuclein aggregates in a mouse model of Gaucher disease Yanyan Penga, Benjamin Lioua, Venette Inskeepa, Rachel Blackwooda, Sheila Flemingb, Christopher N. Mayhewa, Ying Suna, aCincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, b Northeast Ohio Medical University, Rootstown, OH, United States
Mutations in GBA1, which encodes the lysosomal acid betaglucosidase (GCase), cause GCase deficiency in Gaucher disease (GD) and is the most common genetic risk factor for Parkinson disease (PD). There are no effective treatments available for neuronopathic GD and PD that can stop or slow neurodegeneration. In this study, we evaluated a novel non-invasive cell transplantation therapy in a GD mouse model (9H/PS-NA) exhibiting alphasynuclein aggregation, a key PD-relevant phenotype. A subclass of iPSC-derived neural progenitor cells (NPCs) expresses VLA4 which allows systemically-delivered NPCs to cross the blood-brain-barrier. We established VLA4+ mouse iPSC-derived NPCs harboring lentiviral-mediated overexpression of wild-type human GCase (hGCase). In-vitro, VLA4+ hGCase+ NPCs were expandable without loss of multipotency and secreted GCase which was taken up by lysosomes of adjacent Gba1-null cells. In-vivo efficacy was evaluated in 9H/PS-NA mice. VLA4+ hGCase+ NPCs were intravenously administered by weekly tail-vein injection and mice were analyzed at 14 weeks of age for effects on neuropathic and PD phenotypes. Injected cells engrafted throughout the brain, including thalamus, cortex, brainstem and midbrain, and differentiated into neural lineages. Human GCase protein was detected in the transplanted mouse brains with specific anti-human GCase antibody. Histological analyses of brain sections showed reduced neurodegeneration by Fluoro-Jade C staining in the regions of NPC migration. CNS inflammation, detected by anti-CD68 and anti-GFAP antibodies, was significantly decreased in the brain of transplanted mice. Compared to vehicle treated mice, VLA4+ hGCase+ NPC-transplanted mice showed ~50% reduction of α-synuclein aggregates in the substantia nigra. Together, these results demonstrate the efficacy of noninvasive delivery of iPSC-derived NPCs overexpressing hGCase in GD mouse model and establish the feasibility of combined cell and gene therapy for GBA1-associated PD. This approach provides a potential treatment for both rare and common neurological diseases.
doi:10.1016/j.ymgme.2018.12.295
280 Case control study to identify the prevalence of menstrual and pregnancy complications in women with mucopolysaccharidosis Merlene Peter, Stephanie Cagle, Emory University, Atlanta, GA, United States Mucopolysaccharidosis (MPS) are a group of inherited lysosomal storage disorders which are caused due to deficiencies in enzymes leading to accumulation of glycosaminoglycans. There is extensive literature available on the systemic impact of MPS. However, there is a deficit in the number of publications about the prevalence of gynecological problems in women with MPS. In this study, we aim to identify if there is a difference in the menstrual patterns, gynecological problems, and pregnancy complications in women with MPS in comparison to the control population. The study is designed as a case control study in which the cases are women diagnosed with MPS over the age of 12 who have begun menstruating, and the controls are women over the age of 12 without a diagnosis of MPS. Women who underwent a hematopoietic stem cell transplant were excluded from the study as the drugs used for this procedure could influence menstruation and fertility. The study was conducted in the form of a 34-question survey. The survey is divided into questions regarding demographics, menstruation and pregnancy outcomes. The menstrual questionnaire was scored, and chi square analysis was
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
Medical Center, Mainz, Germany, fNeuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice (CHU), Nice, France, gKU Leuven (Catholic University of Leuven) Department of Neurosciences, VIB - Center for Brain & Disease Research, University Hospitals Leuven - Department of Neurology, Leuven, Belgium, hCopenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, iSanofi Genzyme, Chilly-Mazarin, France, jSanofi Genzyme, Cambridge, MA, United States, kFriedrichBaur-Institut, Department of Neurology Klinikum München, München, Germany; 1Current affiliation: Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, , Cincinnati, OH, United States. Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat avalglucosidase alfa dosing (5, 10, or 20 mg/kg qow) for 6 months were evaluated in NEO1 (NCT01898364) in late-onset Pompe disease patients either treatment-naïve (Naïve) or having received alglucosidase alfa for ≥9 months (Switch). In NEO-EXT (NCT02032524), an ongoing NEO1 extension, long-term safety and pharmacokinetics of repeat avalglucosidase alfa dosing will be monitored over 6 years. Interim safety results after 4.5 years of NEO-EXT are reported here. Mean ages at NEO1 enrollment were: Naïve: 44.8 (SD:20.3, range:20-78) years and Switch: 46.7 (SD:14.1, range:21-68) years. Of the 24 NEO1 participants, 19 entered NEO-EXT (8/10 Naïve 11/14 Switch) 17 are currently participating (7/8 Naïve 10/11 Switch) 2 participants discontinued NEO-EXT (personal reasons). During 2016, all NEOEXT participants switched to avalglucosidase alfa 20 mg/kg qow. By May 2018, total infusions reached 731 (Naïve) and 1174 (Switch) mean infusions were Naïve: 73 (SD:43, range:9-113) and Switch: 84 (SD:40, range:8-118). Mean avalglucosidase alfa exposure duration reached 1025 (SD:611, range:109-1572) days for Naïve and 1179 (SD:570, range:102-1658) days for Switch participants. Treatmentemergent adverse events (AEs) were generally mild across doses. Most frequently reported treatment-related AEs were nausea, fatigue, and headache (3 participants each) and dizziness, dyspnea, erythema, myalgia, muscle spasms, and rash (2 participants each) and are unchanged since the last safety update (WORLDSymposium™ 2018). One Switch participant discontinued NEO1 for a study drug-related serious AE (respiratory distress/chest discomfort) no deaths/life-threatening serious AEs have occurred. Anti-avalglucosidase IgG/IgM antibodies developed in 9/10 Switch (median titer:1600, range:200-51,200) and 9/14 Naïve (median titer:400, range:50-12,800) participants. No patient developed IgE antibodies or tested positive for enzyme activity inhibition. In NEOEXT, the avalglucosidase alfa safety profile is consistent with the initial 6 months’ treatment during NEO1, with no additional participants developing anti-avalglucosidase alfa IgG/IgM antibodies or new allergic reactions. Funding: Sanofi Genzyme.
doi:10.1016/j.ymgme.2018.12.294
279 Intravenous infusion of iPSC-derived neural progenitors expressing GCase ameliorates alpha-synuclein aggregates in a mouse model of Gaucher disease Yanyan Penga, Benjamin Lioua, Venette Inskeepa, Rachel Blackwooda, Sheila Flemingb, Christopher N. Mayhewa, Ying Suna, aCincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, b Northeast Ohio Medical University, Rootstown, OH, United States
Mutations in GBA1, which encodes the lysosomal acid betaglucosidase (GCase), cause GCase deficiency in Gaucher disease (GD) and is the most common genetic risk factor for Parkinson disease (PD). There are no effective treatments available for neuronopathic GD and PD that can stop or slow neurodegeneration. In this study, we evaluated a novel non-invasive cell transplantation therapy in a GD mouse model (9H/PS-NA) exhibiting alphasynuclein aggregation, a key PD-relevant phenotype. A subclass of iPSC-derived neural progenitor cells (NPCs) expresses VLA4 which allows systemically-delivered NPCs to cross the blood-brain-barrier. We established VLA4+ mouse iPSC-derived NPCs harboring lentiviral-mediated overexpression of wild-type human GCase (hGCase). In-vitro, VLA4+ hGCase+ NPCs were expandable without loss of multipotency and secreted GCase which was taken up by lysosomes of adjacent Gba1-null cells. In-vivo efficacy was evaluated in 9H/PS-NA mice. VLA4+ hGCase+ NPCs were intravenously administered by weekly tail-vein injection and mice were analyzed at 14 weeks of age for effects on neuropathic and PD phenotypes. Injected cells engrafted throughout the brain, including thalamus, cortex, brainstem and midbrain, and differentiated into neural lineages. Human GCase protein was detected in the transplanted mouse brains with specific anti-human GCase antibody. Histological analyses of brain sections showed reduced neurodegeneration by Fluoro-Jade C staining in the regions of NPC migration. CNS inflammation, detected by anti-CD68 and anti-GFAP antibodies, was significantly decreased in the brain of transplanted mice. Compared to vehicle treated mice, VLA4+ hGCase+ NPC-transplanted mice showed ~50% reduction of α-synuclein aggregates in the substantia nigra. Together, these results demonstrate the efficacy of noninvasive delivery of iPSC-derived NPCs overexpressing hGCase in GD mouse model and establish the feasibility of combined cell and gene therapy for GBA1-associated PD. This approach provides a potential treatment for both rare and common neurological diseases.
doi:10.1016/j.ymgme.2018.12.295
280 Case control study to identify the prevalence of menstrual and pregnancy complications in women with mucopolysaccharidosis Merlene Peter, Stephanie Cagle, Emory University, Atlanta, GA, United States Mucopolysaccharidosis (MPS) are a group of inherited lysosomal storage disorders which are caused due to deficiencies in enzymes leading to accumulation of glycosaminoglycans. There is extensive literature available on the systemic impact of MPS. However, there is a deficit in the number of publications about the prevalence of gynecological problems in women with MPS. In this study, we aim to identify if there is a difference in the menstrual patterns, gynecological problems, and pregnancy complications in women with MPS in comparison to the control population. The study is designed as a case control study in which the cases are women diagnosed with MPS over the age of 12 who have begun menstruating, and the controls are women over the age of 12 without a diagnosis of MPS. Women who underwent a hematopoietic stem cell transplant were excluded from the study as the drugs used for this procedure could influence menstruation and fertility. The study was conducted in the form of a 34-question survey. The survey is divided into questions regarding demographics, menstruation and pregnancy outcomes. The menstrual questionnaire was scored, and chi square analysis was