Gene Therapy for Huntington’s Disease: The Final Strategy for a Cure?

Byun, Seulgi; Lee, Mijung; Kim, Manho

doi:10.14802/jmd.21006

Cited by 15 publications

(9 citation statements)

References 48 publications

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“…37 Thus, a second trial (GENERATION-HD2) with lower doses of the medication started recruiting patients aged 25-50 years with prodromal or early-manifest HD to assess dose finding and possible efficacy in this population. 37,38 The single-gene nature of HD makes the prospect of "gene silencing" to decrease the amount of huntingtin produced, an attractive therapeutic option. In addition to antisense oligonucleotides therapy, a number of other genetic techniques have been studied in humans, including RNA interference (RNAi) gene therapy 39 and brain penetrant mRNA small molecule splicing modifiers, 40 among many others.…”

Section: Finding the Genementioning

confidence: 99%

“…In addition to antisense oligonucleotides therapy, a number of other genetic techniques have been studied in humans, including RNA interference (RNAi) gene therapy 39 and brain penetrant mRNA small molecule splicing modifiers, 40 among many others. Despite more than 100 clinical trials in HD, 38 only symptomatic medications for the disease have been approved in the past three decades, such as Vmat2 inhibitors 41 . Nevertheless, now, we have a better understanding of the pathophysiology of the disease, we have expanded our knowledge of the genetic and epigenetic factors involved, and the curve of ongoing clinical trials is growing exponentially.…”

Section: The Modern Heritage Of Gene Discoverymentioning

confidence: 99%

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The Huntington's Disease Gene Discovery

Franklin,

Teive,

Tensini

et al. 2024

Movement Disorders

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The gene for Huntington's disease (HD) was discovered in 1993, after an international collaborative initiative that led researchers to remote regions of South America. It was the most remarkable milestone, since George Huntington's initial description. Through the phenomenological discussions led by Jean‐Martin Charcot and Willian Osler, and finally Americo Negrette's reports, which served as the inspiration for the Venezuela Project led by Nancy Wexler, the journey toward discovering the Huntington's disease (HD) gene was marked by substantial efforts. This monumental achievement involved the analysis of more than 18,000 blood samples and gathered dozens of researchers in an integrated effort, enabling the mapping of the gene on chromosome 4 in 1983 and leading, a decade later, to the precise localization and identification of the HTT gene. The discovery of the HD mutation represented a pivotal moment in the field of genetics and neurology, significantly enhancing our understanding of the disease and creating opportunities for future treatments. The progress made and the knowledge gained during this journey catalyzed the development of many innovative molecular techniques that have advanced research in other medical conditions. In this article, the authors celebrate three decades of this memorable event, revisiting the historical aspects, providing insights into the techniques developed, and delving into the paths that ultimately led to the discovery of the HD gene. © 2024 International Parkinson and Movement Disorder Society.

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Section: Finding the Genementioning

confidence: 99%

Section: The Modern Heritage Of Gene Discoverymentioning

confidence: 99%

The Huntington's Disease Gene Discovery

Franklin,

Teive,

Tensini

et al. 2024

Movement Disorders

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“…279 CAG repeats in the HTT gene lead to the appearance of repeated segments of glutamine in the translated protein Huntingtin (Htt). 280 This makes the protein more susceptible to misfolding, resulting in protein aggrega-tion. Consequently, the protein undergoes a loss of its basic functionality.…”

Section: Biomedical Applications Of Bioinspired Gene Delivery Systems...mentioning

confidence: 99%

“…DNA repair pathways have been recognized by genome-wide association studies as moderators of somatic instability and disease progression in HD and other repeat expansion diseases . CAG repeats in the HTT gene lead to the appearance of repeated segments of glutamine in the translated protein Huntingtin (Htt) . This makes the protein more susceptible to misfolding, resulting in protein aggregation.…”

Section: Biomedical Applications Of Bioinspired Gene Delivery Systems...mentioning

confidence: 99%

Bioinspired Approaches for Central Nervous System Targeted Gene Delivery

Kumar,

Karim,

Sweety

et al. 2023

ACS Appl. Bio Mater.

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Disorders of the central nervous system (CNS) which include a wide range of neurodegenerative and neurological conditions have become a serious global issue. The presence of CNS barriers poses a significant challenge to the progress of designing effective therapeutic delivery systems, limiting the effectiveness of drugs, genes, and other therapeutic agents. Natural nanocarriers present in biological systems have inspired researchers to design unique delivery systems through biomimicry. As natural resource derived delivery systems are more biocompatible, current research has been focused on the development of delivery systems inspired by bacteria, viruses, fungi, and mammalian cells. Despite their structural potential and extensive physiological function, making them an excellent choice for biomaterial engineering, the delivery of nucleic acids remains challenging due to their instability in biological systems. Similarly, the efficient delivery of genetic material within the tissues of interest remains a hurdle due to a lack of selectivity and targeting ability. Considering that gene therapies are the holy grail for intervention in diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's Disease, and Huntington's disease, this review centers around recent advances in bioinspired approaches to gene delivery for the prevention of CNS disorders.

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“…Drug-based therapy involves symptomatic treatment through various therapeutic drugs [ 41 ]. HD therapeutic development and advancement that modulates the m HTT level through genetic transfer is one of the most important strategies to ameliorate the disease [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

Irfan

Khanam²,

Karmakar³

et al. 2022

Brain Sciences

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Background: Huntington’s disease is an inherited autosomal dominant trait neuro-degenerative disorder caused by changes (mutations) of a gene called huntingtin (htt) that is located on the short arm (p) of chromosome 4, CAG expansion mutation. It is characterized by unusual movements, cognitive and psychiatric disorders. Objective: This review was undertaken to apprehend biological pathways of Huntington’s disease (HD) pathogenesis and its management by nature-derived products. Natural products can be lucrative for the management of HD as it shows protection against HD in pre-clinical trials. Advanced research is still required to assess the therapeutic effectiveness of the known organic products and their isolated compounds in HD experimental models. Summary: Degeneration of neurons in Huntington’s disease is distinguished by progressive loss of motor coordination and muscle function. This is due to the expansion of CAG trinucleotide in the first exon of the htt gene responsible for neuronal death and neuronal network degeneration in the brain. It is believed that the factors such as molecular genetics, oxidative stress, excitotoxicity, mitochondrial dysfunction, neuroglia dysfunction, protein aggregation, and altered UPS leads to HD. The defensive effect of the natural product provides therapeutic efficacy against HD. Recent reports on natural drugs have enlightened the protective role against HD via antioxidant, anti-inflammatory, antiapoptotic, and neurofunctional regulation.

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Gene Therapy for Huntington’s Disease: The Final Strategy for a Cure?

Cited by 15 publications

References 48 publications

The Huntington's Disease Gene Discovery

The Huntington's Disease Gene Discovery

Bioinspired Approaches for Central Nervous System Targeted Gene Delivery

Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

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