International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 252-263 http://medscipublisher.com/index.php/ijmms 260 directly targeting pathogenic genes, such as APP, PSEN1, and APOE, gene therapy can potentially halt or even reverse the progression of AD, rather than merely alleviating symptoms. Techniques like CRISPR/Cas9 have shown promise in preclinical models, where they have successfully reduced amyloid-beta production and improved cognitive functions. Additionally, the development of advanced delivery systems, including viral vectors and nanotechnology-based approaches, has enhanced the precision and efficacy of gene therapies in reaching target brain regions while minimizing off-target effects. Despite the promising developments, several challenges remain that must be addressed through future research. First, improving the safety and efficiency of gene delivery systems is crucial, particularly in overcoming the blood-brain barrier and achieving sustained gene expression without adverse effects. Additionally, the potential for off-target effects with gene-editing technologies like CRISPR/Cas9 must be minimized through advancements in vector design and targeting accuracy. Research should also focus on identifying new therapeutic targets beyond amyloid-beta and tau, including pathways related to neuroinflammation, oxidative stress, and synaptic dysfunction, which could offer broader treatment options for AD. Moreover, personalized gene therapy approaches that consider individual genetic profiles, environmental factors, and lifestyle choices could enhance the efficacy and safety of these treatments, providing tailored interventions for patients. Translating the advances in gene therapy for AD from the laboratory to the clinic involves significant hurdles. Regulatory challenges, ethical considerations, and the high costs associated with gene therapy development are substantial barriers to widespread clinical adoption. Long-term studies are required to evaluate the efficacy, safety, and durability of gene therapies in diverse patient populations. Additionally, the integration of gene therapy with other treatment modalities, such as pharmacotherapy and lifestyle interventions, will be critical in achieving comprehensive and effective care for AD patients. Collaboration between researchers, clinicians, regulatory bodies, and industry partners will be essential to overcome these obstacles and ensure that gene therapy becomes a viable and accessible option for those affected by AD. In conclusion, while significant challenges remain, the prospects of gene therapy in Alzheimer's disease are promising, offering the potential to fundamentally change the treatment landscape for this devastating condition. Continued research, innovation, and collaboration will be key to realizing the full potential of gene therapy in AD, ultimately leading to more effective and personalized treatments for patients. Acknowledgments The authors express gratitude to the two anonymous peer reviewers for their feedback. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Adji A., Widjaja J., Wardani V., Muhammad A., Handajani F., Putra H., and Rahman F., 2022, A review of CRISPR Cas9 for Alzheimer's disease: treatment strategies and could target APOE e4, APP, and PSEN-1 Gene using CRISPR cas9 prevent the patient from alzheimer's disease?, Open Access Macedonian Journal of Medical Sciences, 10(F): 745-57. https://doi.org/10.3889/oamjms.2022.9053 Almkvist O., and Graff C., 2021, The APOE ε4 allele affects cognitive functions differently in carriers of APP mutations compared to carriers of PSEN1 mutations in Autosomal-Dominant Alzheimer's disease, Genes, 12(12): 1954. https://doi.org/10.3390/genes12121954 PMid:34946903 PMCid:PMC8701239 Annu A., Rehman S., Nabi B., Sartaj A., Baboota S., Md S., Sahoo P., and Ali J., 2022, Nanoparticle mediated gene therapy: a trailblazer armament to fight CNS disorders, Current Medicinal Chemistry, 30(3): 304-315. https://doi.org/10.2174/0929867329666220105122318 PMid:34986767 Arora S., Sharma D., Layek B., and Singh J., 2021, A review of brain-targeted nonviral gene-based therapies for the treatment of Alzheimer's disease, Molecular Pharmaceutics, 18(12): 4237-4255. https://doi.org/10.1021/acs.molpharmaceut.1c00611
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