Direct neuronal reprogramming : emerging therapeutic strategies for neurodegenerative disorders
Tyagi, Arooja ; Prabhu, Vijendra ; Agarwal, Prasoon LU
and Kumar, Praveen
(2026)
In Annals of Medicine
58(1).
- Abstract
Background: Treatment of brain injuries and neurodegenerative disorders is a critical challenge due to poor regenerative capabilities of the central nervous system. The current therapeutic strategies are primarily focussed on treating the symptoms than addressing the core issue of loss of neurons. Despite advances in stem cell therapies and surgical alternatives, they are not always successful due to challenges like immune rejection and limited efficacy. Direct neuronal reprogramming of endogenous somatic cells is a promising approach to restore lost neurons. This review evaluates traditional reprogramming techniques and their limitations, explores novel in-vivo strategies that address older problems, and analyse clinical trial outcomes... (More)
Background: Treatment of brain injuries and neurodegenerative disorders is a critical challenge due to poor regenerative capabilities of the central nervous system. The current therapeutic strategies are primarily focussed on treating the symptoms than addressing the core issue of loss of neurons. Despite advances in stem cell therapies and surgical alternatives, they are not always successful due to challenges like immune rejection and limited efficacy. Direct neuronal reprogramming of endogenous somatic cells is a promising approach to restore lost neurons. This review evaluates traditional reprogramming techniques and their limitations, explores novel in-vivo strategies that address older problems, and analyse clinical trial outcomes to identify key knowledge gaps to guide future research. Discussion: Traditional neuronal reprogramming is based on in-vitro ectopic expression of lineage-specific transcription factors. To overcome hurdles posed by in-vitro reprogramming, such as insertional mutagenesis, and variable efficiency, in-vivo approaches have emerged. These techniques employ small molecules, nonviral gene delivery, and CRISPR-based activation to reduce protocol complexity and improve cell survival. Combined methodologies integrate transcription factor cocktails with epigenetic modifiers, microRNAs, and neurotrophic factors, and show further enhancements. Despite these advances, translation to clinical applications has been modest. Early-phase trials report limited functional improvements and highlight risks of off-target effects, inconsistent delivery specificity, and unresolved immunogenicity Conclusions: Direct neuronal reprogramming offers a viable strategy for replenishing neuronal cell mass in neurodegenerative diseases and brain injuries through autologous therapy. Novel in-vivo and combined approaches show promise in addressing the shortcomings of traditional methods. However, further preclinical validation, comprehensive safety assessments, and uniform frameworks are essential for clinical translation. Future studies should prioritize refining delivery platforms, minimizing off-target reprogramming events, and developing robust biomarkers to monitor conversion efficiency and functional outcomes.
(Less)
- author
- Tyagi, Arooja
; Prabhu, Vijendra
; Agarwal, Prasoon
LU
and Kumar, Praveen
- organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- autologous therapy, Cell plasticity, CRISPR, personalised medicine, small molecules, transdifferentiation
- in
- Annals of Medicine
- volume
- 58
- issue
- 1
- article number
- 2654230
- publisher
- Taylor & Francis
- external identifiers
-
- pmid:41986248
- scopus:105035819036
- ISSN
- 0785-3890
- DOI
- 10.1080/07853890.2026.2654230
- language
- English
- LU publication?
- yes
- id
- f810b275-b1d6-4ea5-af4e-e2bf3fc78342
- date added to LUP
- 2026-05-25 11:48:57
- date last changed
- 2026-05-26 03:22:24
@article{f810b275-b1d6-4ea5-af4e-e2bf3fc78342,
abstract = {{<p>Background: Treatment of brain injuries and neurodegenerative disorders is a critical challenge due to poor regenerative capabilities of the central nervous system. The current therapeutic strategies are primarily focussed on treating the symptoms than addressing the core issue of loss of neurons. Despite advances in stem cell therapies and surgical alternatives, they are not always successful due to challenges like immune rejection and limited efficacy. Direct neuronal reprogramming of endogenous somatic cells is a promising approach to restore lost neurons. This review evaluates traditional reprogramming techniques and their limitations, explores novel in-vivo strategies that address older problems, and analyse clinical trial outcomes to identify key knowledge gaps to guide future research. Discussion: Traditional neuronal reprogramming is based on in-vitro ectopic expression of lineage-specific transcription factors. To overcome hurdles posed by in-vitro reprogramming, such as insertional mutagenesis, and variable efficiency, in-vivo approaches have emerged. These techniques employ small molecules, nonviral gene delivery, and CRISPR-based activation to reduce protocol complexity and improve cell survival. Combined methodologies integrate transcription factor cocktails with epigenetic modifiers, microRNAs, and neurotrophic factors, and show further enhancements. Despite these advances, translation to clinical applications has been modest. Early-phase trials report limited functional improvements and highlight risks of off-target effects, inconsistent delivery specificity, and unresolved immunogenicity Conclusions: Direct neuronal reprogramming offers a viable strategy for replenishing neuronal cell mass in neurodegenerative diseases and brain injuries through autologous therapy. Novel in-vivo and combined approaches show promise in addressing the shortcomings of traditional methods. However, further preclinical validation, comprehensive safety assessments, and uniform frameworks are essential for clinical translation. Future studies should prioritize refining delivery platforms, minimizing off-target reprogramming events, and developing robust biomarkers to monitor conversion efficiency and functional outcomes.</p>}},
author = {{Tyagi, Arooja and Prabhu, Vijendra and Agarwal, Prasoon and Kumar, Praveen}},
issn = {{0785-3890}},
keywords = {{autologous therapy; Cell plasticity; CRISPR; personalised medicine; small molecules; transdifferentiation}},
language = {{eng}},
number = {{1}},
publisher = {{Taylor & Francis}},
series = {{Annals of Medicine}},
title = {{Direct neuronal reprogramming : emerging therapeutic strategies for neurodegenerative disorders}},
url = {{http://dx.doi.org/10.1080/07853890.2026.2654230}},
doi = {{10.1080/07853890.2026.2654230}},
volume = {{58}},
year = {{2026}},
}