RNA-targeting antisense therapies in neurodegenerative diseases

Abstract

Neurodegenerative diseases are a group of chronic and debilitating disorders characterized by the gradual degeneration of neuronal structure, resulting in their impaired functionality. The World Health Organization has predicted neurodegenerative diseases to become the second most prevalent cause of death in the global population within the next 20 years. Treatments for most neurodegenerative diseases only focus on improving patients' quality of life rather than being able to fully change the course of the diseases. Genetic risk factors have been identified for a large variety of neurodegenerative diseases. This makes them an appealing target for many genetic therapies, including therapeutic antisense oligonucleotides, which utilize RNA-targeting approaches.

Antisense oligonucleotides are short nucleic acid structures that can be synthesized and chemically modified so that they bind to predetermined RNA molecules and alter gene expression, RNA splicing, or protein synthesis to achieve medical benefits. The U.S. Food and Drug Administration has licensed three antisense oligonucleotide drugs for the treatment of neurodegenerative diseases and more drugs have shown promising results in clinical trials. Challenges remain in delivering antisense oligonucleotides safely to the central nervous system through biological barriers. Multiple bioconjugation strategies, such as antibody conjugates and aptamers are currently investigated to solve these issues. Promising trials of antisense oligonucleotide-based drugs have been halted due to a lack of efficiency and worrisome safety profiles. Ongoing research is essential to refine these therapies, expand their applicability to various conditions, and assess their long-term safety and efficacy.

In this thesis, the achievements, possibilities, and obstacles related to the evolving field of antisense oligonucleotide therapies for neurodegenerative diseases are discussed with a focus on drug delivery, chemical modifications of antisense oligonucleotides, and recent advances made in the development of antisense oligonucleotide therapies for Spinal muscular atrophy, Amyotrophic lateral sclerosis, and Huntington’s disease.