AI Article Synopsis
- * Intrathecal (IT) delivery of AAV vectors can bypass some of these problems but has limitations in distribution and potential liver toxicity.
- * Researchers identified improved AAV capsids through testing in non-human primates, which demonstrated better retention in the spinal cord and lower distribution to the liver, making them promising candidates for spinal cord gene therapies compared to traditional AAV9.
Article Abstract
Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405149 | PMC |
| http://dx.doi.org/10.1016/j.ymthe.2024.05.040 | DOI Listing |
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