Christine Í Dali1, Caroline Sevin2, Ingeborg Krägeloh-Mann3, Roberto Giugliani4, Norio Sakai5, James Wu6, Margaret Wasilewski7. 1. Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address: cid@dadlnet.dk. 2. Neuropediatrics Unit, Bicêtre Hospital, Paris, France. Electronic address: caroline.sevin@inserm.fr. 3. Department of Neuropediatrics, University Children's Hospital Tübingen, Tübingen, Germany. Electronic address: ingeborg.kraegeloh-mann@med.uni-tuebingen.de. 4. Medical Genetics Service, HCPA, Department of Genetics, UFRGS, and INAGEMP, Porto Alegre, Brazil. Electronic address: rgiugliani@hcpa.edu.br. 5. Osaka University Hospital, Osaka, Japan. Electronic address: norio@ped.med.osaka-u.ac.jp. 6. Shire, a member of the Takeda group of companies, Lexington, MA, USA. Electronic address: james.wu100@yahoo.com. 7. Shire, a member of the Takeda group of companies, Lexington, MA, USA. Electronic address: mwasilewski@mac.com.
Abstract
BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). METHODS: Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). RESULTS: No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. CONCLUSION: Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.
BACKGROUND:Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). METHODS: Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). RESULTS: No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. CONCLUSION: Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.
Authors: Christine Í Dali; Samuel Groeschel; Mihai Moldovan; Mohamed H Farah; Ingeborg Krägeloh-Mann; Margaret Wasilewski; Jing Li; Norman Barton; Christian Krarup Journal: Ann Clin Transl Neurol Date: 2020-12-17 Impact factor: 4.511
Authors: Daphne H Schoenmakers; Shanice Beerepoot; Sibren van den Berg; Laura Adang; Annette Bley; Jaap-Jan Boelens; Francesca Fumagalli; Wim G Goettsch; Sabine Grønborg; Samuel Groeschel; Peter M van Hasselt; Carla E M Hollak; Caroline Lindemans; Fanny Mochel; Peter G M Mol; Caroline Sevin; Ayelet Zerem; Ludger Schöls; Nicole I Wolf Journal: Orphanet J Rare Dis Date: 2022-02-14 Impact factor: 4.123
Authors: Marjo S van der Knaap; Joshua L Bonkowsky; Adeline Vanderver; Raphael Schiffmann; Ingeborg Krägeloh-Mann; Enrico Bertini; Genevieve Bernard; Seyed Ali Fatemi; Nicole I Wolf; Elise Saunier-Vivar; Robert Rauner; Hanka Dekker; Pieter van Bokhoven; Peter van de Ven; Prisca S Leferink Journal: Neurol Genet Date: 2022-02-02
Authors: Jonathan B Rosenberg; Alvin Chen; Bishnu P De; Jonathan P Dyke; Douglas J Ballon; Sebastien Monette; Rodolfo J Ricart Arbona; Stephen M Kaminsky; Ronald G Crystal; Dolan Sondhi Journal: Hum Gene Ther Date: 2021-03-30 Impact factor: 4.793
Authors: Francesca Fumagalli; Valeria Calbi; Maria Grazia Natali Sora; Maria Sessa; Cristina Baldoli; Paola Maria V Rancoita; Francesca Ciotti; Marina Sarzana; Maddalena Fraschini; Alberto Andrea Zambon; Serena Acquati; Daniela Redaelli; Vanessa Attanasio; Simona Miglietta; Fabiola De Mattia; Federica Barzaghi; Francesca Ferrua; Maddalena Migliavacca; Francesca Tucci; Vera Gallo; Ubaldo Del Carro; Sabrina Canale; Ivana Spiga; Laura Lorioli; Salvatore Recupero; Elena Sophia Fratini; Francesco Morena; Paolo Silvani; Maria Rosa Calvi; Marcella Facchini; Sara Locatelli; Ambra Corti; Stefano Zancan; Gigliola Antonioli; Giada Farinelli; Michela Gabaldo; Jesus Garcia-Segovia; Laetitia C Schwab; Gerald F Downey; Massimo Filippi; Maria Pia Cicalese; Sabata Martino; Clelia Di Serio; Fabio Ciceri; Maria Ester Bernardo; Luigi Naldini; Alessandra Biffi; Alessandro Aiuti Journal: Lancet Date: 2022-01-22 Impact factor: 79.321