A study published in Genes & Diseases reports that researchers from East China University of Science and Technology, Belief Biomed Inc, and Yunnan University engineered a novel viral vector, AAVT42 that efficiently delivers therapeutic genes to the brain, restoring memory and protecting neuronal structures in multiple models of Alzheimer’s disease.

The research team utilized directed evolution to develop AAVT42, a recombinant adeno-associated virus (rAAV) with a high affinity for neurons. Unlike standard vectors that often "leak" into non-neuronal cells, the AAVT42 vector demonstrated superior neuronal tropism, widespread hippocampal distribution, and a robust safety profile.

The researchers used the AAVT42 vector to deliver BDNF directly into the hippocampus of three different Alzheimer’s mouse models - amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg - covering a range of pathologies, including amyloid-beta plaques and tau tangles, and in aged cynomolgus monkey models. In all of these models, BDNF treatment was shown to achieve a significant cognitive rescue, restoring spatial working memory and learning abilities as evidenced by improved performance in the Morris water maze and Barnes maze tests. The treatment also facilitated structural repair by restoring dendritic complexity and stabilizing MAP-2, a critical protein that maintains the communication branches of neurons damaged by neurodegeneration.

High-throughput RNA sequencing revealed that BDNF drives these improvements by suppressing the harmful BMP signaling pathway, leading to the up-regulation of genes essential for synaptic plasticity, memory formation, and dendritic morphogenesis, such as Vgf and Shank1. Together, these findings demonstrate that AAVT42-mediated BDNF delivery effectively repairs the physical and molecular architecture of the brain, offering neuroprotection against Alzheimer's disease pathology.

Similar results were observed in aged cynomolgus monkeys. The vector achieved extensive and specific neuronal transduction without triggering adverse immune responses or neuroinflammation - the two major hurdles in central nervous system gene therapy. These findings suggest that "the high transduction efficiency of AAVT42, combined with its safer profile in aged primates, facilitates its potential application in future clinical trials for neurological disorders."

This study concludes that local, high-efficiency delivery of BDNF via AAVT42 offers a robust strategy for early-stage intervention, potentially mitigating the cognitive decline associated with Alzheimer’s and other neurodegenerative disorders.

Reference

Title of the original paper
Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI : https://doi.org/10.1016/j.gendis.2025.101649

Funding Information:
National Key Research and Development Program of China (No. 2021YFC2700803)
National Natural Science Foundation of China (No.82471501, 82360226)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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