image: (A) Generation of the novel AAVT42 vector by directed evolution and in vivo screening. The cap genes of AAV1, AAV2, AAV3B, AAV4, and AAV6-9 were mixed, after digestion, denaturation, and reannealing, the shuffled novel AAV cap genes were generated, which were then inserted behind the rep gene and established a library of AAV viral particles. These viruses were injected intravenously in mice, after skeletal muscle isolation, AAV variants displaying tissue tropism were collected, and the corresponding cap genes were recovered by polymerase chain reaction, which were re-cloned into infectious plasmids, forming the viral particles. Then in vivo screening in the skeletal muscle was conducted again for further enrichment, characterization, and the sequencing validation of the novel variant. . (B) The schematic of stereotactic AAV injection in mice. (C) Representative confocal microscope images of GFP expression in the mice dorsal hippocampus, and the cell nuclei were marked with DAPI (blue). DG, dentate gyrus; CA1, cornu ammonis 1; CA3, cornu ammonis 3. Yellow arrows indicated GFP-positive dendrites. (D) Quantification analysis of GFP fluorescent intensity in the dorsal hippocampus. Both the left and right half of the dorsal hippocampus of each mouse were quantified (dorsal hippocampus: AAV9-GFP = 1342 ± 359, n = 5 mice; AAVT42-GFP = 2916 ± 354, n = 5 mice, with two injection sites per mouse, AAV9-GFP versus AAVT42-GFP, ∗∗P = 6.8 × 10−3). (E) The schematic of stereotactic AAV injection in monkey brain. (F) Confocal images showed GFP-positive cells, which colocalized with neuron marker (NeuN, red) in the hippocampus of monkeys after AAVT42-GFP injection. (G) Representative confocal microscope images of antibodies to GFP, NeuN, astrocyte marker GFAP, and microglia marker Iba1 in monkey hippocampus. AAV, adeno-associated virus; GFP, green fluorescent protein.
Credit: Siqi Tang, Wenshu Luo, Shihao Wu, Meng Yuan, Jiashuo Wen, Guoshen Zhong, Leshan Shen, Wei Jiang, Cheng Cheng, Xia Wu, Xiao Xiao
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.
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