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Intrathecal delivery of recombinant human arylsulfatase A in children with late-infantile metachromatic leukodystrophy
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
symptoms even with slower infusion rates. All patients underwent dose specific rapid 3 bags 12-steps desensitization protocol, using opioids to control shivering, with good response. Despite symptoms being immunoglobulin E-mediated, Cytokine release syndrome can be a concomitant mechanism to explain the symptomatology. Enzyme replacement therapy (ERT) for the treatment of Lysosomal diseases (LD) has greatly improved the prognosis of these disorders. Infusionrelated reactions (IRR) to ERT can occur and can be severe, precluding further ERT. Management of these reactions with desensitization can provide first line therapy and permit continued ERT. doi:10.1016/j.ymgme.2015.12.230
73 Intrathecal delivery of recombinant human arylsulfatase A in children with late-infantile metachromatic leukodystrophy Christine Dalia, Caroline Sevinb, Joachim Riethmüllerc, Roberto Giuglianid, Christopher Troedsone, Parul Bhargavaf, Anna Wijatykf, a Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark, b Neuropediatrics Unit, Bicêtre Hospital, Paris, France, cDepartment of Neuropediatrics, University Children's Hospital Tübingen, Tübingen, Germany, dMedical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil, e The Children's Hospital at Westmead, Sydney, Australia, fShire, Lexington, MA, United States Metachromatic leukodystrophy (MLD) is characterized by a deficiency in arylsulfatase A (ASA), resulting in sulfatide build-up in the central and peripheral nervous system. In late-infantile (LI)-MLD, children experience neurodegenerative symptoms before eventual death. With no approved treatments, experimental approaches include gene or enzyme replacement therapy. This phase 1/2, nonrandomized, open-label, 40-week, dose-escalation study evaluated the safety of recombinant human ASA (rhASA), administered via an intrathecal drug delivery device (IDDD), in children with LI-MLD (NCT01510028). We describe data from three treatment cohorts (10, 30 or 100 mg rhASA every other week). Children with MLD (age b12 years, first symptoms at age ≤30 months) who were ambulatory at screening were eligible. Eighteen children (mean ± SD age, 43.7 ± 23.0 months; 7 girls) were enrolled (6 per cohort). Over the 40 weeks, 11 patients had ≥1 investigator-judged treatmentrelated AE, of whom ≥3 experienced rash, pyrexia or increased gamma-glutamyltransferase levels. No treatment-related serious AE (SAE) were reported: 13 patients experienced ≥1 SAE, of whom 3 had nasopharyngitis, viral infection or febrile convulsion. Five individuals reported 10 incidents of IDDD-related SAE including ≥2 individuals reporting device failure or dislocation. Mean ± SD changes (baseline to week 40) in Gross Motor Function Measure 88 (GMFM-88) total scores (%) were: rhASA 10 mg, −29.2 ± 24.5%; 30 mg, −27.7 ± 17.8%; 100 mg, −19.0 ± 16.1%. Children with baseline GMFM-88 N 40 receiving rhASA 100 mg had less decline in motor function (mean ± SD change, −18.3 ± 17.9%) compared with the 10 and 30 mg cohorts (−46.8 ± 9.5% and − 42.2 ± 24.0%, respectively). MRI MLD severity score appeared stable in the 100 mg group (mean ± SD change from baseline to week 40, −2.6 ± 3.9), and increased in the 10 and 30 mg cohorts (mean ± SD changes 11.0 ± 4.1 and 5.7 ± 8.1, respectively). In conclusion, intrathecal rhASA was generally well tolerated with an apparent efficacy signal at the 100 mg dose. This supports its continued development as a potential therapy for patients with LIMLD.
doi:10.1016/j.ymgme.2015.12.231
74 Different cyclodextrins for the treatment of Niemann-Pick disease type C Cristin Davidsona, Yonatan Fishmana, Istvan Puskasb, Julliana Szemanb, Tomas Sohajdab, Jakub Sikorac, Marie T. Vanierd, Lajos Szenteb, Steven U. Walkleya, Kostantin Dobrenisa, aAlbert Einstein College of Medicine, Bronx, NY, United States, bCycloLab, Budapest, Hungary, cInstitute of Inherited Metabolic Disorders, Praha, Czech Republic, dInstitut National de la Santé et de la Recherche Médicale, Lyon, France Niemann-Pick type C (NPC) disease is a fatal, neurovisceral, lysosomal disorder characterized by accumulation of cholesterol and gangliosides, particularly prominent in the central nervous system. Clinical manifestations include a relentless, progressive neurological decline and at present, NPC is incurable. Administration of (2hydroxypropyl)-beta-cyclodextrin (HPBCD) has provided the greatest disease amelioration in NPC animal models to date, albeit with ototoxicity, although the mechanism of action remains unresolved. To explore therapeutic alternatives and mechanistic insights 9 diverse cyclodextrins (CDs), including the one currently in clinical trials for NPC, were compared for in vivo efficacy on brain and liver, for ototoxicity and for complexation properties toward relevant lipid metabolites. Npc1-/- and wildtype (Wt) mice were treated from 7 to 21 days of age with CDs and tissues analyzed for reductions in cholesterol storage and ganglioside accumulation. To evaluate ototoxicity, hearing tests were performed on Wt mice administered different CDs. Extensive in vitro tests compared interaction of different CDs with cholesterol, gangliosides and other lipids. In vivo mouse studies revealed significant variation in storage reduction and ototoxicity with different CDs. Importantly, sulfobutylether-beta-CD and sulfobutylether-gamma-CD showed efficacy with increased safety, though long term efficacy studies are needed to fully judge their therapeutic suitability relative to HPBCD. In vitro studies showed partial correlation between efficacy or ototoxicity and capacity to interact with accumulating compounds, but suggest that previous models of CD-mediated clearance of accumulating metabolites may be overly simplistic and involve more than a simple interaction between CD and cholesterol. These findings provide important insights and direction for identification of superior CDs for treatment of NPC disease. Funding generously provided by Dana’s Angels Research Trust, Hide & Seek Foundation, Ara Parseghian Medical Research Foundation, and National Institutes of Health (R01 NS053677 and P30 HD071593). doi:10.1016/j.ymgme.2015.12.232
75 Pathogenic cascade downstream of NEU1 regulated lysosomal exocytosis Alessandra d'Azzo, St. Jude Children's Research Hospital, Memphis, TN, United States By studying molecular mechanisms of pathogenesis in the lysosomal disease sialidosis we uncovered physiological processes controlled by the lysosomal sialidase NEU1 and its substrates. One such process is calcium-regulated lysosomal exocytosis (LEX). NEU1 negatively regulate LEX by restraining the number of lysosomes docked at the PM, prior to fuse with the PM and release their contents. Deficiency of NEU1 results in exacerbated LEX, with deleterious consequences for ECM and PM integrity, and overall tissue homeostasis. We reasoned that unrestrained LEX in different cells and tissues could underlie many of the phenotypic abnormalities in sialidosis. We found that the brain of Neu1-/- mice develop
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
symptoms even with slower infusion rates. All patients underwent dose specific rapid 3 bags 12-steps desensitization protocol, using opioids to control shivering, with good response. Despite symptoms being immunoglobulin E-mediated, Cytokine release syndrome can be a concomitant mechanism to explain the symptomatology. Enzyme replacement therapy (ERT) for the treatment of Lysosomal diseases (LD) has greatly improved the prognosis of these disorders. Infusionrelated reactions (IRR) to ERT can occur and can be severe, precluding further ERT. Management of these reactions with desensitization can provide first line therapy and permit continued ERT. doi:10.1016/j.ymgme.2015.12.230
73 Intrathecal delivery of recombinant human arylsulfatase A in children with late-infantile metachromatic leukodystrophy Christine Dalia, Caroline Sevinb, Joachim Riethmüllerc, Roberto Giuglianid, Christopher Troedsone, Parul Bhargavaf, Anna Wijatykf, a Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark, b Neuropediatrics Unit, Bicêtre Hospital, Paris, France, cDepartment of Neuropediatrics, University Children's Hospital Tübingen, Tübingen, Germany, dMedical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil, e The Children's Hospital at Westmead, Sydney, Australia, fShire, Lexington, MA, United States Metachromatic leukodystrophy (MLD) is characterized by a deficiency in arylsulfatase A (ASA), resulting in sulfatide build-up in the central and peripheral nervous system. In late-infantile (LI)-MLD, children experience neurodegenerative symptoms before eventual death. With no approved treatments, experimental approaches include gene or enzyme replacement therapy. This phase 1/2, nonrandomized, open-label, 40-week, dose-escalation study evaluated the safety of recombinant human ASA (rhASA), administered via an intrathecal drug delivery device (IDDD), in children with LI-MLD (NCT01510028). We describe data from three treatment cohorts (10, 30 or 100 mg rhASA every other week). Children with MLD (age b12 years, first symptoms at age ≤30 months) who were ambulatory at screening were eligible. Eighteen children (mean ± SD age, 43.7 ± 23.0 months; 7 girls) were enrolled (6 per cohort). Over the 40 weeks, 11 patients had ≥1 investigator-judged treatmentrelated AE, of whom ≥3 experienced rash, pyrexia or increased gamma-glutamyltransferase levels. No treatment-related serious AE (SAE) were reported: 13 patients experienced ≥1 SAE, of whom 3 had nasopharyngitis, viral infection or febrile convulsion. Five individuals reported 10 incidents of IDDD-related SAE including ≥2 individuals reporting device failure or dislocation. Mean ± SD changes (baseline to week 40) in Gross Motor Function Measure 88 (GMFM-88) total scores (%) were: rhASA 10 mg, −29.2 ± 24.5%; 30 mg, −27.7 ± 17.8%; 100 mg, −19.0 ± 16.1%. Children with baseline GMFM-88 N 40 receiving rhASA 100 mg had less decline in motor function (mean ± SD change, −18.3 ± 17.9%) compared with the 10 and 30 mg cohorts (−46.8 ± 9.5% and − 42.2 ± 24.0%, respectively). MRI MLD severity score appeared stable in the 100 mg group (mean ± SD change from baseline to week 40, −2.6 ± 3.9), and increased in the 10 and 30 mg cohorts (mean ± SD changes 11.0 ± 4.1 and 5.7 ± 8.1, respectively). In conclusion, intrathecal rhASA was generally well tolerated with an apparent efficacy signal at the 100 mg dose. This supports its continued development as a potential therapy for patients with LIMLD.
doi:10.1016/j.ymgme.2015.12.231
74 Different cyclodextrins for the treatment of Niemann-Pick disease type C Cristin Davidsona, Yonatan Fishmana, Istvan Puskasb, Julliana Szemanb, Tomas Sohajdab, Jakub Sikorac, Marie T. Vanierd, Lajos Szenteb, Steven U. Walkleya, Kostantin Dobrenisa, aAlbert Einstein College of Medicine, Bronx, NY, United States, bCycloLab, Budapest, Hungary, cInstitute of Inherited Metabolic Disorders, Praha, Czech Republic, dInstitut National de la Santé et de la Recherche Médicale, Lyon, France Niemann-Pick type C (NPC) disease is a fatal, neurovisceral, lysosomal disorder characterized by accumulation of cholesterol and gangliosides, particularly prominent in the central nervous system. Clinical manifestations include a relentless, progressive neurological decline and at present, NPC is incurable. Administration of (2hydroxypropyl)-beta-cyclodextrin (HPBCD) has provided the greatest disease amelioration in NPC animal models to date, albeit with ototoxicity, although the mechanism of action remains unresolved. To explore therapeutic alternatives and mechanistic insights 9 diverse cyclodextrins (CDs), including the one currently in clinical trials for NPC, were compared for in vivo efficacy on brain and liver, for ototoxicity and for complexation properties toward relevant lipid metabolites. Npc1-/- and wildtype (Wt) mice were treated from 7 to 21 days of age with CDs and tissues analyzed for reductions in cholesterol storage and ganglioside accumulation. To evaluate ototoxicity, hearing tests were performed on Wt mice administered different CDs. Extensive in vitro tests compared interaction of different CDs with cholesterol, gangliosides and other lipids. In vivo mouse studies revealed significant variation in storage reduction and ototoxicity with different CDs. Importantly, sulfobutylether-beta-CD and sulfobutylether-gamma-CD showed efficacy with increased safety, though long term efficacy studies are needed to fully judge their therapeutic suitability relative to HPBCD. In vitro studies showed partial correlation between efficacy or ototoxicity and capacity to interact with accumulating compounds, but suggest that previous models of CD-mediated clearance of accumulating metabolites may be overly simplistic and involve more than a simple interaction between CD and cholesterol. These findings provide important insights and direction for identification of superior CDs for treatment of NPC disease. Funding generously provided by Dana’s Angels Research Trust, Hide & Seek Foundation, Ara Parseghian Medical Research Foundation, and National Institutes of Health (R01 NS053677 and P30 HD071593). doi:10.1016/j.ymgme.2015.12.232
75 Pathogenic cascade downstream of NEU1 regulated lysosomal exocytosis Alessandra d'Azzo, St. Jude Children's Research Hospital, Memphis, TN, United States By studying molecular mechanisms of pathogenesis in the lysosomal disease sialidosis we uncovered physiological processes controlled by the lysosomal sialidase NEU1 and its substrates. One such process is calcium-regulated lysosomal exocytosis (LEX). NEU1 negatively regulate LEX by restraining the number of lysosomes docked at the PM, prior to fuse with the PM and release their contents. Deficiency of NEU1 results in exacerbated LEX, with deleterious consequences for ECM and PM integrity, and overall tissue homeostasis. We reasoned that unrestrained LEX in different cells and tissues could underlie many of the phenotypic abnormalities in sialidosis. We found that the brain of Neu1-/- mice develop