International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 252-263 http://medscipublisher.com/index.php/ijmms 257 5 Current Research and Clinical Trials 5.1 Preclinical studies Preclinical studies in animal models of Alzheimer's disease (AD) have provided valuable insights into the potential efficacy of gene therapy. These models, primarily transgenic mice that express human genes associated with familial AD, have been instrumental in evaluating the effects of gene therapy interventions. For instance, the use of adeno-associated virus (AAV) vectors to deliver neuroprotective genes such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) has shown promise in reducing amyloid-beta plaque formation and enhancing neuronal survival (Tuszynski et al., 2015). Similarly, gene therapy approaches targeting the tau protein have demonstrated efficacy in reducing tau pathology and improving cognitive function in these models (Tedeschi et al., 2021). These successes highlight the potential of gene therapy as a treatment for AD. Despite the promising results in animal models, translating these findings to human clinical trials has been fraught with challenges. One major issue is the difference in disease pathology between animals and humans, which can result in therapies that are effective in animal models failing to show similar efficacy in humans. For example, the complexity of the human brain and the multifactorial nature of AD mean that therapies targeting a single pathway may not be sufficient to halt disease progression (Banik et al., 2015). Additionally, the blood-brain barrier (BBB) poses a significant hurdle in delivering gene therapies effectively to the human brain, a challenge that is less pronounced in animal models (LaFerla and Green, 2012). 5.2 Completed and ongoing clinical trials Several clinical trials have been initiated to test the safety and efficacy of gene therapies in AD patients. Notably, early trials focused on the delivery of NGF to the brain using AAV vectors. Although these trials demonstrated the safety of the approach, the results were inconclusive regarding cognitive benefits, partly due to challenges in achieving adequate vector delivery and gene expression in target areas (Castle et al., 2020). More recent trials are exploring the use of advanced delivery methods, including convection-enhanced delivery and MRI-guided stereotactic surgery, to improve the accuracy and efficacy of gene delivery (Tuszynski et al., 2015). The outcomes of these clinical trials have highlighted several challenges in the application of gene therapy for AD. One of the primary challenges has been the limited spread of the therapeutic gene within the brain, resulting in suboptimal engagement of target neurons. Furthermore, the heterogeneity of AD, both in terms of genetic mutations and disease progression, complicates the design of clinical trials and the interpretation of results (Yiannopoulou et al., 2019). Despite these challenges, ongoing trials continue to refine gene delivery techniques and explore combination therapies to enhance therapeutic outcomes. 5.3 Emerging research trends To address the challenges observed in earlier trials, researchers are investigating new viral vectors and delivery methods that can achieve more widespread and targeted gene expression in the brain. For example, the development of modified AAV vectors with enhanced tropism for neurons and the use of non-viral delivery systems such as nanoparticles are promising approaches under investigation (Chen et al., 2020). Additionally, advances in real-time imaging techniques, such as MRI-guided delivery, are being incorporated into clinical trial designs to improve the precision of gene therapy administration. Emerging research is also focusing on identifying novel therapeutic targets for gene therapy in AD. Beyond amyloid-beta and tau, researchers are exploring the potential of targeting neuroinflammation, synaptic dysfunction, and oxidative stress, all of which play critical roles in AD pathogenesis (Owens et al., 2021). These efforts are aimed at developing multifaceted gene therapy approaches that can address the various aspects of AD pathology, offering a more comprehensive treatment strategy. 6 Challenges and Limitations of Gene Therapy in AD 6.1 Technical and biological barriers One of the most significant technical challenges in applying gene therapy for Alzheimer's disease (AD) is the blood-brain barrier (BBB). The BBB is a selective barrier that protects the brain from potentially harmful
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