Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review

Abstract

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; curative genetic therapy; disease-modifying treatment; spinal muscular atrophy.

Figure 1

Study selection flowchart following the PRISMA method, detailing the number of studies identified, included, and excluded at each stage, along with the applied exclusion criteria.

Figure 2

The review analysis highlights two principal gene therapy approaches for neurodegenerative diseases (NDDs). Therapies with curative intent involve the introduction of a corrective gene or oligonucleotide using adeno-associated viral (AAV) vectors or gene-editing techniques (CRISPR-Cas and antisense oligonucleotides), targeting diseases caused by specific genetic mutations. In contrast, therapies with a cell-survival-promoting intent utilize adenoviral vectors or stem cell transplantation to deliver factors that enhance cellular survival. This latter approach can be applied to both monogenic and polygenic neurodegenerative diseases, offering broader therapeutic potential.