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Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates

Kousaku Ohno1, Lluis Samaranch1, Piotr Hadaczek1

  • 1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94103, USA.

Molecular Therapy. Methods & Clinical Development
|January 23, 2019
PubMed

Insights

Magnetic resonance imaging (MRI) effectively monitors intrathecal infusions in nonhuman primates. MRI revealed that delivery via the cerebellomedullary cistern, especially combined with lumbar injection, ensures optimal infusate distribution throughout the brain and spinal cord.

Area of Science:

  • Neuroscience
  • Medical Imaging
  • Biotechnology

Background:

  • Intrathecal infusions are crucial for delivering therapeutics to the central nervous system.
  • Monitoring the distribution and kinetics of infusates is essential for optimizing delivery strategies.
  • Nonhuman primates serve as valuable models for studying central nervous system delivery methods.

Purpose of the Study:

  • To evaluate the utility of Magnetic Resonance Imaging (MRI) for real-time monitoring of intrathecal infusions in nonhuman primates.
  • To analyze the distribution patterns and cerebrospinal fluid (CSF) clearance kinetics of infusates based on different administration routes.
  • To determine the most effective routes for achieving broad infusate distribution within the brain and spinal cord.

Main Methods:

  • Adeno-associated virus (AAV) vectors were spiked with gadoteridol, a gadolinium-based MRI contrast agent.
  • Infusions were administered via multiple routes: cerebromedullary cistern, lumbar, combined cerebromedullary and lumbar, and intracerebroventricular.
  • MRI was used for real-time visualization of infusate distribution and subsequent kinetic analysis of vector clearance from CSF.

Main Results:

  • MRI enabled real-time visualization of intrathecal infusions across all tested delivery routes.
  • Cerebellomedullary cistern delivery, particularly when combined with lumbar injection, demonstrated broad and effective distribution in both the brain and spinal cord.
  • Intracerebroventricular injection primarily resulted in cortical distribution with minimal spinal coverage, while lumbar injection alone showed limited and unreliable distribution.

Conclusions:

  • MRI is a valuable tool for optimizing intrathecal infusion delivery by providing real-time monitoring and detailed distribution analysis.
  • The route of administration significantly impacts infusate distribution within the CSF, with cerebellomedullary cistern delivery being highly effective.
  • Understanding these distribution patterns is critical for the successful development and application of intrathecal therapies.
Keywords:
AAV vectorcerebrospinal fluidcisterna magnagene therapyintracerebroventricularintrathecal infusionlumbarmagnetic resonance imagingnon-human primatespharmacokinetics

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