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A - Viral Vector Development -> AAV Vectors – Virology and Vectorology, Vectorology, and Engineering

1247: Natural AAV2 Variants Demonstrate Stronger Neurotropism, Penetrance of the Blood-Brain Barrier, and Differential Transduction of Brain Regions Compared to AAV9

Type: Poster Session

Poster Board Number: 1247
Presentation Details
Session Title: Thursday Poster Session
Start Time: 5/18/2023 12:00
End Time: 5/18/2023 14:00

There is a continuing need to discover and/or engineer novel adeno-associated virus (AAV) capsids for human gene therapy. Most discovery pursuits are focused on overcoming the patient’s immune system and delivering transgenes efficiently to specific tissue targets. Capsids of different serotypes possess diverse tropism profiles, resulting from variations in the amino acids present on the capsid surface. Multiple studies have used rational design to engineer capsids with desired transduction patterns. Random mutagenesis and machine learning approaches, coupled with directed evolution have enabled researchers to test large libraries of candidate capsids. These efforts have uncovered capsids that outperform those tested in clinical trials and commercially-approved AAV vectors. However, naturally circulating AAV variants remain an untapped reservoir for capsid discovery. Among a library of human-isolated 86 AAV2 variants that show equal or better packaging yields than prototypical AAV2, we identified seven variants tentatively named v46, v56, v67, v81, v224, v326, and v358, that demonstrated strong transduction following intrahippocampal injections in adult mice. In addition, we observed that the variants conferred differential transgene expression in separate structures of the hippocampus. These capsids possess 12-15 residues that are different from AAV2, mainly clustered within variable regions IV-VIII. Four of the seven capsid variants share variable region residues with AAV2.v66, a neurotropic AAV2 variant we previously identified. We have been exploring the mechanisms that underpin how these variants can confer neurotropism that rivals AAV9. Our preliminary data show that following facial vein injections of neonatal mice, the seven variants can traverse the blood-brain barrier and exhibit strong transduction of the thalamus, a structure that is an important target for neuronopathic lysosomal storage diseases but fails to be strongly transduced by AAV9 with systemic delivery. Our ongoing work explores whether the unique biodistributions achieved by our AAV2 variants are a result of cell type-specific transduction. Our findings support the notion that natural variants can serve as useful sources for gene therapy capsids.

Sophia Liu1,2, Thomas Leland1,2, Manish Muhuri1, Anoushka Lotun1, Meiyu Xu1, Guangchao Xu3, Li Luo3, Wanru Qin3, Ran He1, Qin Su1, Jun Xie1, Yu-Quan Wei3, Phillip WL Tai1,4, Guangping Gao1,4

1UMass Chan Medical School, Worcester, MA,2Co-first Authors, Worcester, MA,3Sichuan University, Chengdu, China,4Co-corresponding Authors, Worcester, MA
 S. Liu: None.

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