Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes

Danielle A. Simmons; Sridhar Selvaraj; Tingshuo Chen; Gloria Cao; Talita Souto Camelo; Tyne L.M. McHugh; Selena Gonzalez; Renata M. Martin; Juste Simanauskaite; Nobuko Uchida; Matthew H. Porteus; Frank M. Longo

doi:10.1016/j.omtm.2025.101415

Molecular Therapy: Methods & Clinical Development (Mar 2025)

Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes

Danielle A. Simmons,
Sridhar Selvaraj,
Tingshuo Chen,
Gloria Cao,
Talita Souto Camelo,
Tyne L.M. McHugh,
Selena Gonzalez,
Renata M. Martin,
Juste Simanauskaite,
Nobuko Uchida,
Matthew H. Porteus,
Frank M. Longo

Affiliations

Danielle A. Simmons: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author: Danielle A. Simmons, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sridhar Selvaraj: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Tingshuo Chen: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Gloria Cao: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Talita Souto Camelo: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Tyne L.M. McHugh: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Selena Gonzalez: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Renata M. Martin: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Juste Simanauskaite: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Nobuko Uchida: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Matthew H. Porteus: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Frank M. Longo: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA

DOI: https://doi.org/10.1016/j.omtm.2025.101415
Journal volume & issue: Vol. 33, no. 1
p. 101415

Abstract

Read online

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: https://www.cell.com/molecular-therapy-family/methods/home

About the journal

Abstract

Keywords