Restoring Parkin function: an AAV gene therapy approach for early-onset Parkinson’s disease
- 1Spark Therapeutics, Philadelphia, PA, United States
- 2Roche Innovation Center (RICP), Philadelphia, PA, United States
- 3National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States
Abstract
Biallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinson’s disease (EOPD). Parkin is a crucial component of the PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration. We investigated Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD. We validated phosphorylated ubiquitin Ser65 (pUbSer65) as an indicator of PINK1-Parkin pathway initiation/activation. We evaluated AAV-mediated PRKN replacement (AAV-Parkin) in a Parkin knockout neuroblastoma cell (SH-SY5Y cells) and feasibility of delivery in mouse and rat models. Our research showed pUbSer65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement restored these pUbSer65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid (also referred as Spk100), finding Ef1a and Synapsin1 (Syn1) were most effective for transducing relevant cell populations, including dopaminergic neurons, in the SN of mice without causing adverse effects. These findings established a short-term well-tolerated vector dose and an optimal capsid-promoter combination. Our results establish foundational feasibility and short-term tolerability, supporting the potential of AAV-Parkin gene therapy as a promising candidate for further preclinical development for Parkin-deficient EOPD.
Related
- Fejerin promotes autophagy via the PINK1-Parkin pathway and is protective against Parkinson’s disease pathology
- Beyond motor recovery: subthalamic nucleus deep brain stimulation may improve blinking and dry eye symptoms without restoring tear film homeostasis in Parkinson's disease.
- Electroacupuncture inhibits pyroptosis to improve motor function in an MPTP-induced mouse model of Parkinson’s disease
- Effects of dual-task training on health-related quality of life and cognitive function in people with Parkinson’s disease: a systematic review and meta-analysis
- MUSIC‐PD: A Delphi‐Derived, Culturally Adaptable Music Therapy Protocol for Parkinson's Disease Rehabilitation
BibTeX
@article{basu2026restoring,
title = {{Restoring Parkin function: an AAV gene therapy approach for early-onset Parkinson’s disease}},
author = {Sambuddha Basu and Tyler G. Demarest and Nicholas J. Gattone and Alexandra J. Gilsrud and Brittany Wicks and Apeksha Khatiwada and Mohammad Nayal and Renee Gentzel and Daniel M. Cohen and Eric W. Kostuk and Derek P. Narendra and Pedro Gonzalez-Alegre and Maria-Grazia Biferi and Elizabeth A. Ramsburg},
journal = {Frontiers in Molecular Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1939065},
url = {https://doi.org/10.3389/fnmol.2026.1939065},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Restoring Parkin function: an AAV gene therapy approach for early-onset Parkinson’s disease
AU - Sambuddha Basu
AU - Tyler G. Demarest
AU - Nicholas J. Gattone
AU - Alexandra J. Gilsrud
AU - Brittany Wicks
AU - Apeksha Khatiwada
AU - Mohammad Nayal
AU - Renee Gentzel
AU - Daniel M. Cohen
AU - Eric W. Kostuk
AU - Derek P. Narendra
AU - Pedro Gonzalez-Alegre
AU - Maria-Grazia Biferi
AU - Elizabeth A. Ramsburg
PY - 2026
DA - 2026/10/21
JO - Frontiers in Molecular Neuroscience
DO - 10.3389/fnmol.2026.1939065
UR - https://doi.org/10.3389/fnmol.2026.1939065
AB - Biallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinson’s disease (EOPD). Parkin is a crucial component of the PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration. We investigated Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD. We validated phosphorylated ubiquitin Ser65 (pUbSer65) as an indicator of PINK1-Parkin pathway initiation/activation. We evaluated AAV-mediated PRKN replacement (AAV-Parkin) in a Parkin knockout neuroblastoma cell (SH-SY5Y cells) and feasibility of delivery in mouse and rat models. Our research showed pUbSer65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement restored these pUbSer65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid (also referred as Spk100), finding Ef1a and Synapsin1 (Syn1) were most effective for transducing relevant cell populations, including dopaminergic neurons, in the SN of mice without causing adverse effects. These findings established a short-term well-tolerated vector dose and an optimal capsid-promoter combination. Our results establish foundational feasibility and short-term tolerability, supporting the potential of AAV-Parkin gene therapy as a promising candidate for further preclinical development for Parkin-deficient EOPD.
SN - 1662-5099
ER -