International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 252-263 http://medscipublisher.com/index.php/ijmms 256 these strategies may offer new hope in combating the devastating effects of AD, though careful consideration of the associated risks and ethical issues remains paramount. 4 Current Strategies in Gene Therapy for Alzheimer’s Disease 4.1 Viral vector-based therapies Viral vectors have been at the forefront of gene therapy due to their high efficiency in delivering genetic material into target cells. Among these, adeno-associated virus (AAV) and lentivirus are particularly prominent in the context of Alzheimer’s disease (AD) research. AAV vectors are favored for their ability to infect both dividing and non-dividing cells, making them suitable for targeting neurons, which are largely non-dividing. AAV vectors are also known for their low immunogenicity and long-term expression of therapeutic genes (Ralph et al., 2006; Honig, 2018). Lentiviral vectors, on the other hand, have the capacity to integrate into the host genome, leading to stable and long-term expression of the therapeutic gene. This feature is particularly useful for chronic conditions like AD, where sustained gene expression is critical (Kumar and Woon-Khiong, 2011). Despite the advantages, viral vectors face significant challenges in gene therapy for AD. One major challenge is the blood-brain barrier (BBB), which limits the efficient delivery of these vectors to the central nervous system (CNS). Strategies to overcome this include the development of vectors that can cross the BBB or the use of invasive methods like intracranial injections (Butt et al., 2022). Additionally, there are concerns regarding the potential for insertional mutagenesis with lentiviral vectors, where the integration of the viral genome into the host DNA could disrupt important genes and lead to oncogenesis. Advances in vector design, such as the use of integration-deficient lentiviral vectors, are being explored to mitigate these risks (Kumar and Woon-Khiong, 2011). 4.2 Non-viral gene delivery systems Non-viral gene delivery systems, such as nanoparticles and liposomes, have gained traction due to their safety profile and flexibility. Nanoparticles can be engineered to bypass the BBB and deliver genes directly to the brain, reducing systemic toxicity and improving the specificity of gene delivery (Arora et al., 2021). Liposomes, which are lipid-based carriers, can encapsulate nucleic acids and protect them from degradation, allowing for efficient delivery to target cells. Both nanoparticles and liposomes can be modified with targeting ligands to enhance their delivery to specific cell types, including neurons affected by AD. Recent advances in nanotechnology have led to the development of multifunctional nanoparticles that not only deliver genes but also facilitate their controlled release in the brain. These nanoparticles can be designed to respond to specific stimuli, such as pH or temperature changes, which are characteristic of diseased tissues, ensuring that the therapeutic genes are released only where they are needed (Ediriweera et al., 2021). Furthermore, nanotechnology allows for the co-delivery of multiple therapeutic agents, such as genes and drugs, which could provide a more comprehensive approach to treating AD by targeting multiple pathways simultaneously (Annu et al., 2022). 4.3 Gene therapy with stem cells Gene therapy combined with stem cell technology offers a promising strategy for neuroregeneration in AD. Induced pluripotent stem cells (iPSCs) can be genetically modified to overexpress neuroprotective genes and then transplanted into the brain to replace lost or damaged neurons. These gene-modified stem cells not only integrate into the existing neural network but also provide a continuous source of therapeutic proteins that can mitigate the progression of AD (Haridhasapavalan et al., 2019). The use of iPSCs, which are derived from a patient’s own cells, circumvents the ethical and immunological issues associated with embryonic stem cells. By using gene-editing tools like CRISPR/Cas9, iPSCs can be corrected for any genetic mutations before being differentiated into neurons and transplanted back into the patient’s brain. This approach not only aims to replace lost neurons but also to correct the underlying genetic causes of AD, offering a potentially curative treatment (Komatsu et al., 2019). However, the clinical translation of these therapies requires further research to ensure the safety and efficacy of the genetically modified cells, particularly in terms of their long-term integration and function in the brain.
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