Mol Neurobiol. 2024 Jul 3. doi: 10.1007/s12035-024-04285-3. Online ahead of print.

ABSTRACT

Alzheimer’s disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current treatments focus on the management of symptoms, as no effective therapy has been approved to modify the underlying disease process. Gene therapy is a promising approach that can offer disease-modifying treatment for AD, targeting various aspects of the pathophysiology of the disease. This review presents a comprehensive overview of the current state of gene therapy research for AD, with a specific focus on clinical trials and preclinical studies that have used nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), apolipoprotein E2 (APOE2), and human telomerase reverse transcriptase (hTERT) as therapeutic gene therapy approaches. These gene targets have shown potential to alleviate the neuropathology of AD in animal studies and have demonstrated feasibility and safety in non-human primates. Despite the failure of the NGF gene therapy approach in clinical trials, we have reviewed and highlighted the reported findings and evaluations from the trials. Furthermore, the review included the conclusions of postmortem brain tissue analysis of AD patients who received NGF gene therapy. The goal is to learn from the failed trials and improve the approach in the future. Although gene therapy shows promise, it faces several challenges and limitations, including optimizing gene delivery methods, enhancing safety and efficacy profiles, and determining long-term results. This review contributes to the growing body of literature on innovative treatments for AD and highlights the need for more research and development to advance gene therapy as a viable treatment option for AD.

PMID:38958888 | DOI:10.1007/s12035-024-04285-3