Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial
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Published:2022-09
Issue:9
Volume:28
Page:1813-1822
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ISSN:1078-8956
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Container-title:Nature Medicine
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language:en
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Short-container-title:Nat Med
Author:
Baloh Robert H., Johnson J. Patrick, Avalos Pablo, Allred Peggy, Svendsen Soshana, Gowing Genevieve, Roxas Kristina, Wu AmandaORCID, Donahue Becky, Osborne Sheryl, Lawless George, Shelley Brandon, Wheeler Koral, Prina Carolyn, Fine Dana, Kendra-Romito Tami, Stokes Haniah, Manoukian Vicki, Muthukumaran Abirami, Garcia Leslie, Bañuelos Maria G., Godoy MarlesaORCID, Bresee Catherine, Yu Hong, Drazin Doniel, Ross Lindsey, Naruse Robert, Babu Harish, Macklin Eric A., Vo Ashley, Elsayegh Ashraf, Tourtellotte Warren, Maya Marcel, Burford Matthew, Diaz FrankORCID, Patil Chirag G., Lewis Richard A., Svendsen Clive N.ORCID
Abstract
AbstractAmyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3–5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.
Funder
California Institute for Regenerative Medicine
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
Reference54 articles.
1. Jaiswal, M. K. Riluzole and edaravone: a tale of two amyotrophic lateral sclerosis drugs. Med. Res. Rev. 39, 733–748 (2019). 2. Harms, M. B. & Baloh, R. H. Clinical neurogenetics: amyotrophic lateral sclerosis. Neurol. Clin. 31, 929–950 (2013). 3. Mueller, C. et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020). 4. Miller, T. et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020). 5. Du, Z.-W. et al. Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat. Commun. 6, 6626 (2015).
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