Journal article
Intracerebroventricular SPAST-AAV9 gene therapy prevents the manifestation of symptoms in a mouse model of SPG4 Hereditary Spastic Paraplegia
Molecular therapy, v 34(3), Forthcoming
26 Nov 2025
PMID: 41311060
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Hereditary Spastic Paraplegia type 4 is characterized by gait impairments, progressive spasticity and weakness of the lower limbs, resulting from degeneration of the corticospinal tracts. The disease is caused by mutations of the SPAST gene, which encodes a major isoform of spastin called M87 and a minor isoform called M1. Owing to its N-terminal hydrophobic domain not shared by M87, M1 is the isoform that becomes toxic when mutated. Loss-of-function of either M1 or M87 or both may also play a role in the disease, sensitizing corticospinal motor neurons to the toxicity of mutant M1. Here we pursued silence-and-replace gene therapy, which addresses both gain-of-toxicity and loss-of-function components of the disease. We generated an adeno-associated serotype 9 viral vector containing micro-RNA to stop the expression from the endogenous SPAST gene and cDNA to express healthy human M1 and M87. The vector was introduced by intracerebroventricular injections into newborn pups of SPAST-C448Y, a mouse model of the disease that expresses human mutant spastin and displays adult-onset corticospinal degeneration and gait defects. The treatment successfully replaced both isoforms of endogenous spastin with healthy spastin, at physiological levels, and prevented the onset and progression of corticospinal degeneration and gait defects.
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Details
- Title
- Intracerebroventricular SPAST-AAV9 gene therapy prevents the manifestation of symptoms in a mouse model of SPG4 Hereditary Spastic Paraplegia
- Creators
- Emanuela Piermarini - Drexel UniversityShrobona Guha - Drexel UniversityLiang Qiang - Drexel UniversityHeather Gray-Edwards - University of Massachusetts Chan Medical SchoolMiguel Sena-Esteves - University of Massachusetts Chan Medical SchoolPeter W Baas (Corresponding Author) - Drexel University
- Publication Details
- Molecular therapy, v 34(3), Forthcoming
- Publisher
- Elsevier
- Number of pages
- 14
- Grant note
- Spastic Paraplegia FoundationNIH (National Institute of Neurological Disorders and Stroke): R01 NS118177, R01 NS115977 Cure SPG4 FoundationLilly and Blair FoundationSPG4 CureMaurya Koduri Foundation
We acknowledge the assistance in this work of Koray Kirimtay for the M1 antibody testing and Angela Altadonna, Kendra Case, Skandha Ramakrishan, Neha Mohan, and Sean Vansen (all from Drexel University) for helping with the sera and tissues collection. This work is supported by separate grants from the Spastic Paraplegia Foundation to E.P., P.W.B., and L.Q., and from the NIH (National Institute of Neurological Disorders and Stroke) to P.W.B. (R01 NS118177) and L.Q. (R01 NS115977) . Generous additional funding and ongoing support at all levels were provided by the Cure SPG4 Foundation, The Lilly and Blair Foundation, SPG4 Cure for Jack Laidlaw, and the Maurya Koduri Foundation. This work is dedicated to the children living with SPG4 Hereditary Spastic Paraplegia and the limitless dedication of their parents to find a cure. The authors reserve the right to intellectual properties related to future commercialization of the vector or a modification of it for future clinical trials on patients.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:001709760100001
- Scopus ID
- 2-s2.0-105025122892
- Other Identifier
- 991022133562804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental