Abstract | December 19, 2022
Gene Therapy Approach in Alzheimer’s Disease
Learning Objectives
- Describe the data available on the gene therapy approach in AD utilizing BDNF, NGF and APOE2
- Discuss the different roles of BDNF, NGF and APOE2 in Alzheimer's Disease
- Describe how the gene therapy approach can halt, prevent or delay the progression of AD
Background: Alzheimer’s Disease (AD) is a neurodegenerative disease presenting with progressive dementia, beta-amyloid (Aβ) plaques, and neurofibrillary tangles. This debilitating disease leads to negative symptoms including the inability to recognize loved ones, a significant reduction in memory retention, and severe confusion. There are no current therapies able to halt, prevent or delay AD pathology. Researchers are investigating potential disease-modifying therapies for AD utilizing a gene therapy approach to deliver the gene of interest which include 1) Brain-derived neurotrophic factor (BDNF), 2) Nerve Growth Factor (NGF), and 3) Apolipoprotein E2 (APOE2).
Methods: All data collected were obtained using published peer-reviewed journal articles from PubMed. The keywords utilized for this search included “Alzheimer’s Disease + Gene Therapy”, “BDNF + Gene Therapy + Alzheimer’s Disease”, “APOE + Gene Therapy + Alzheimer’s Disease”, and “NGF + Gene Therapy + Alzheimer’s Disease”. The information provided in this review was not limited to a particular time frame.
Results: BDNF functions in developing and maintaining synaptic plasticity and is the key regulator for long-term potentiation. In non-human primates, BDNF gene therapy demonstrated improved behavioral deficits, synaptic plasticity, and memory. A phase 1 clinical trial is ongoing for AAV2-BDNF. NGF is involved in differentiation and has been shown to promote survival of basal forebrain cholinergic neurons. In a phase 1 trial, AAV2-NGF gene therapy demonstrated long-term safety in patients with mild to moderate AD. In a phase 2 trial, AAV2-NGF delivery was feasible and well tolerated; however, no benefit on cognition was found after 24 months. The APOE gene on chromosome 19 encodes apoE protein (three isoforms – APOE2/3/4), which has a significant role in neurological diseases. The E4 isoform is associated with an increased risk of AD; however, the E2 isoform is linked to lower risk and later age of onset. APOE2 administration in in vivo animal studies has shown a neuroprotective effect and a reduction in Aβ plaque aggregation. A phase I clinical trial is ongoing for AAVrh.10hAPOE2 gene therapy in APOE4 homozygotes with AD.
Conclusion: Studies involving the gene therapies of BDNF, NGF, and APOE2 have shown much promise in preclinical studies. Research investigating these potential disease-modifying therapeutics for AD continues to grow. The ongoing clinical trials will allow a better understanding of the gene therapy approach to prevent AD.
References:
- https://medlineplus.gov/genetics/understanding/therapy/genetherapy/
- https://learn.genetics.utah.edu/content/genetherapy/
- https://health.ucsd.edu/news/releases/Pages/2021-02-18-first-in-human-clinical-trial-to-assess-gene-therapy-for-alzheimers-disease.aspx
