Merjane, Jessica;
Chung, Roger;
Patani, Rickie;
Lisowski, Leszek;
(2023)
Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno-associated viral vectors.
Medicinal Research Reviews
10.1002/med.21937.
(In press).
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Abstract
Despite the devastating clinical outcome of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), its etiology remains mysterious. Approximately 90% of ALS is characterized as sporadic, signifying that the patient has no family history of the disease. The development of an impactful disease modifying therapy across the ALS spectrum has remained out of grasp, largely due to the poorly understood mechanisms of disease onset and progression. Currently, ALS is invariably fatal and rapidly progressive. It is hypothesized that multiple factors can lead to the development of ALS, however, treatments are often focused on targeting specific familial forms of the disease (10% of total cases). There is a strong need to develop disease modifying treatments for ALS that can be effective across the full ALS spectrum of familial and sporadic cases. Although the onset of disease varies significantly between patients, there are general disease mechanisms and progressions that can be seen broadly across ALS patients. Therefore, this review explores the targeting of these widespread disease mechanisms as possible areas for therapeutic intervention to treat ALS broadly. In particular, this review will focus on targeting mechanisms of defective protein homeostasis and RNA processing, which are both increasingly recognized as design principles of ALS pathogenesis. Additionally, this review will explore the benefits of gene therapy as an approach to treating ALS, specifically focusing on the use of adeno-associated virus (AAV) as a vector for gene delivery to the CNS and recent advances in the field.
| Type: | Article |
|---|---|
| Title: | Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno-associated viral vectors |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/med.21937 |
| Publisher version: | https://doi.org/10.1002/med.21937 |
| Language: | English |
| Additional information: | © 2023 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, adeno-associated virus, amyotrophic lateral sclerosis, gene therapy, proteostasis, RNA binding proteins, RNA-BINDING PROTEINS, FRONTOTEMPORAL LOBAR DEGENERATION, UBIQUITIN-PROTEASOME SYSTEM, MOTOR-NEURON DISEASE, ANTISENSE OLIGONUCLEOTIDES, HEXANUCLEOTIDE REPEAT, NONHUMAN-PRIMATES, PHASE-TRANSITIONS, INTRON RETENTION, MESSENGER-RNA |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167609 |
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