Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases
Abstract
Efforts to develop neurotrophic factors to restore function and protect dying neurons in chronic neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD) have been attempted for decades. Despite abundant data establishing nonclinical proof-of-concept, significant delivery issues have precluded the successful translation of this concept to the clinic. The development of AAV2 viral vectors to deliver therapeutic genes has emerged as a safe and effective means to achieve sustained, long-term, targeted, bioactive protein expression. Thus, it potentially offers a practical means to solve those long-standing delivery/translational issues associated with neurotrophic factors. Data are presented for two AAV2 viral vector constructs expressing one of two different neurotrophic factors: nerve growth factor (NGF) and neurturin (NRTN). One (AAV2-NGF; aka CERE-110) is being developed as a treatment to improve the function and delay further degeneration of cholinergic neurons in the nucleus basalis of Meynert, the degeneration of which has been linked to cognitive deficits in AD. The other (AAV2-NRTN; aka CERE-120) is similarly being developed to treat the degenerating nigrostriatal dopamine neurons and major motor deficits in PD. The data presented here demonstrate: (1) 2-year, targeted, bioactive-protein in monkeys, (2) persistent, bioactive-protein throughout the life-span of the rat, and (3) accurately targeted bioactive-protein in aged rats, with (4) no safety issues or antibodies to the protein detected. They also provide empirical guidance to establish parameters for human dosing and collectively support the idea that gene transfer may overcome key delivery obstacles that have precluded successful translation of neurotrophic factors to the clinic. More specifically, they also enabled the AAV-NGF and AAV-NRTN programs to advance into ongoing multi-center, double-blind clinical trials in AD and PD patients.
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AAV vector administration to the CNS has an excellent safety and efficacy profile.
“AAV vector administration to the CNS has an excellent safety and efficacy profile.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [55]
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- Authors
- Herzog, C. D., Bishop, K. M., Brown, L., Wilson, A., Kordower, J. H., & Bartus, R. T.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Bartus, Raymond T.
- ORCID
- Kordower, Jeffrey H.
- Venue
- Drug Delivery and Translational Research
- Published
- 2011-08-20
- Volume
- 1
- Issue
- 5
- Pages
- 361-382
- ISSN
- 2190-393X (ISSN-L)
- 2190-3948
- OpenAlex
- W2012001030
- Cited by
- 29
- References
- 74
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 7 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Drug Delivery and Translational Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- neurotrophic factors, gene transfer, nerve growth factor, neurturin, Alzheimer's disease, Parkinson's disease, nucleus basalis of Meynert, nigrostriatal dopaminergic neurons, targeted gene delivery, clinical translation
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