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Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus

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Summary

Intrathecal delivery of self-complementary adeno-associated virus-9 (scAAV9) showed widespread but variable biodistribution in macaques. Vector DNA and GFP expression were highest in the spinal cord and dorsal root ganglia, with limited brain neuronal transduction.

Keywords:
AAV9animal studiesbiodistributioncentral nervous systemgene therapyintrathecaltransduction

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Area of Science:

  • Neuroscience
  • Gene Therapy
  • Viral Vector Biodistribution

Background:

  • Adeno-associated virus (AAV) vectors are promising for gene therapy.
  • Intrathecal delivery aims to target the central nervous system.
  • Understanding AAV biodistribution is crucial for therapeutic efficacy.

Purpose of the Study:

  • To assess the biodistribution and expression of self-complementary AAV9 (scAAV9) after intrathecal administration in juvenile macaques.
  • To compare central nervous system (CNS) and systemic biodistribution.
  • To evaluate the suitability of this vector for neurologic diseases requiring widespread brain neuronal expression.

Main Methods:

  • Intrathecal infusion of scAAV9-chicken β-actin promoter-green fluorescent protein (GFP) via lumbar puncture or intracisterna magna in cynomolgus macaques.
  • Necropsy at 28 days post-infusion.
  • Quantification of vector DNA using droplet digital polymerase chain reaction (ddPCR).
  • Assessment of GFP expression using in situ hybridization, Meso Scale Discovery (MSD) electrochemiluminescence, and immunohistochemistry (IHC).

Main Results:

  • Widespread but variable biodistribution of vector DNA and GFP expression.
  • Highest concentrations in the spinal cord, dorsal root ganglia (DRG), and liver.
  • Low vector DNA and GFP levels in most brain regions.
  • Transduction and expression primarily in perivascular astrocytes in the brain, with minimal neuronal transduction.
  • Significant GFP expression observed in hepatocytes, myocytes, cardiomyocytes, spinal cord lower motor neurons, and DRG sensory neurons.

Conclusions:

  • scAAV9 intrathecal delivery resulted in widespread biodistribution but limited transduction in brain neurons.
  • The current scAAV9-capsid/expression cassette combination may not be optimal for neurologic diseases requiring broad brain neuronal expression.
  • This vector system might be more suitable for diseases involving secreted proteins or those not requiring widespread neuronal transduction in the brain.