2027
Tirgar, Fatemeh; Hosseini, Mina; Alijanpour, Sakineh; Aghanoori, Mohamad-Reza; Alijanpour, Sahar; Mahdavinataj, Hami
Chapter 12 - Gene therapy in Huntington’s disease (HD) Book Section
In: Mansouri, Vahid; Bemanalizadeh, Maryam (Ed.): Gene Therapy in Neurodegenerative Disorders, pp. 311-357, Academic Press, 2027, ISBN: 978-0-443-40467-2.
Abstract | Links | BibTeX | Tags: Antisense oligonucleotides, Gene therapy, Genome editing, Huntington’s disease, RNA interference
@incollection{TIRGAR2027311,
title = {Chapter 12 - Gene therapy in Huntington’s disease (HD)},
author = {Fatemeh Tirgar and Mina Hosseini and Sakineh Alijanpour and Mohamad-Reza Aghanoori and Sahar Alijanpour and Hami Mahdavinataj},
editor = {Vahid Mansouri and Maryam Bemanalizadeh},
url = {https://www.sciencedirect.com/science/article/pii/B9780443404672000117},
doi = {https://doi.org/10.1016/B978-0-443-40467-2.00011-7},
isbn = {978-0-443-40467-2},
year = {2027},
date = {2027-01-01},
booktitle = {Gene Therapy in Neurodegenerative Disorders},
pages = {311-357},
publisher = {Academic Press},
abstract = {Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments, ultimately leading to premature death. Despite its well-defined genetic etiology, including an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene, current therapeutic strategies remain primarily symptomatic, with limited impact on disease progression. Understanding the pathogenic mechanisms of mutant huntingtin (mHTT) protein, including toxic protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and impaired synaptic signaling, has paved the way for molecularly targeted interventions. Gene therapy approaches have emerged as promising disease-modifying strategies, aiming to reduce mHTTexpression, restore cellular homeostasis, and enhance neuronal survival. Antisense oligonucleotides and RNA interference-based therapeutics are at the forefront, while innovative modalities such as CRISPR/Cas genome editing, DNA repair enzyme delivery, and brain-derived neurotrophic factor augmentation are under active exploration. Several clinical trials, including those investigating tominersen, branaplam, and AMT-130, have provided critical insights into the feasibility, efficacy, and safety of gene therapy in HD, though challenges remain regarding target specificity, long-term efficacy, and off-target effects. Preclinical studies in animal models continue to advance the field by refining gene silencing, gene editing, and neuroprotective strategies. This chapter provides a comprehensive overview of the epidemiology, clinical features, and molecular underpinnings of HD, critically examines current and emerging gene therapy approaches, and discusses the translational hurdles that must be addressed to realize their therapeutic potential.},
keywords = {Antisense oligonucleotides, Gene therapy, Genome editing, Huntington’s disease, RNA interference},
pubstate = {published},
tppubtype = {incollection}
}
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments, ultimately leading to premature death. Despite its well-defined genetic etiology, including an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene, current therapeutic strategies remain primarily symptomatic, with limited impact on disease progression. Understanding the pathogenic mechanisms of mutant huntingtin (mHTT) protein, including toxic protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and impaired synaptic signaling, has paved the way for molecularly targeted interventions. Gene therapy approaches have emerged as promising disease-modifying strategies, aiming to reduce mHTTexpression, restore cellular homeostasis, and enhance neuronal survival. Antisense oligonucleotides and RNA interference-based therapeutics are at the forefront, while innovative modalities such as CRISPR/Cas genome editing, DNA repair enzyme delivery, and brain-derived neurotrophic factor augmentation are under active exploration. Several clinical trials, including those investigating tominersen, branaplam, and AMT-130, have provided critical insights into the feasibility, efficacy, and safety of gene therapy in HD, though challenges remain regarding target specificity, long-term efficacy, and off-target effects. Preclinical studies in animal models continue to advance the field by refining gene silencing, gene editing, and neuroprotective strategies. This chapter provides a comprehensive overview of the epidemiology, clinical features, and molecular underpinnings of HD, critically examines current and emerging gene therapy approaches, and discusses the translational hurdles that must be addressed to realize their therapeutic potential.