ArticleThe Journal of clinical investigation2023
Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 43 citations in OpenAlex.
- AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne syndrome.The Journal of clinical investigation · 2026Article
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- Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia.Annals of clinical and translational neurology · 2026Article
- A Head-to-Head Comparison of AAV9 Biodistribution in Mice: Routes of Administration and Age Dependence.Genes · 2026Article
- Neutrophil-initiated nociceptive ingrowth orchestrates inflammation resolution to potentiate bone regeneration.Bone research · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Exploration of a DDX3X Gene Supplementation Therapy Including Expanded Characterization and Novel Findings of Sleep Disturbances inBiological psychiatry global open science · 2025Article
- Cardiomyocyte USP20 alleviates septic cardiomyopathy by deubiquitinating and inhibiting NLRP3 activity.Clinical and translational medicine · 2025Article
- AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Improved AAV9-based gene therapy design forMolecular therapy. Methods & clinical development · 2025Article
- Fetal and Perinatal Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.Annals of the Child Neurology Society · 2025Article
- Gene Therapy of Adrenomyeloneuropathy: Challenges, Target Cells, and Prospectives.Biomedicines · 2025Review
- A father's crusade in rare disease drug development: a case study of Elpida therapeutics and Melpida.Orphanet journal of rare diseases · 2025Article
- IMPC impact on preclinical mouse models.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Expression and distribution of rAAV9 intrathecally administered in juvenile to adolescent mice.Gene therapy · 2025Article
- Article
- Genetic editing of primary human dorsal root ganglion neurons using CRISPR-Cas9.Scientific reports · 2025Article
- Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency.Communications medicine · 2025Article
- Restoring adapter protein complex 4 function with small molecules: an in silico approach to spastic paraplegia 50.Protein science : a publication of the Protein Society · 2025Article
- Riboflavin transporter deficiency:Frontiers in cellular neuroscience · 2025Article
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12 authors at 3 institutions in 1 country.
Funding
Abstract
Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay, and subsequent intellectual disability, secondary microcephaly, and epilepsy. We preformed preclinical studies evaluating an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50 and describe in vitro studies that demonstrate transduction of patient-derived fibroblasts with AAV2/AP4M1, resulting in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1-KO mice were intrathecally (i.t.) injected with 5 × 1011, 2.5 × 1011, or 1.25 × 1011 vector genome (vg) doses of AAV9/AP4M1 at P7-P10 or P90. Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in WT mice, rats, and nonhuman primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1 × 1015 vg. Of note, similar degrees of minimal-to-mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future i.t. AAV studies. These preclinical results identify an acceptably safe and efficacious dose of i.t.-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.