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Intra-CSF AAV9 and AAVrh10 Administration in Nonhuman Primates: Promising Routes and Vectors for Which Neurological
Karim Bey1, Johan Deniaud1, Laurence Dubreil1
1UMR PAnTher 703 INRA/Oniris Animal Pathophysiology and Bio Therapy for Muscle and Nervous System Diseases, Oniris, Nantes-Atlantic College of Veterinary Medicine Food Sciences and Engineering, 44307 Nantes Cedex 03, France.
Summary
Adeno-associated virus (AAV) delivery via lumbar intrathecal catheterization with AAV9 shows superior whole central nervous system targeting in macaques. This method also effectively targets muscles, offering new therapeutic potential for CNS and muscle diseases.
Area of Science:
- Neuroscience
- Gene Therapy
- Virology
Background:
- Efficient central nervous system (CNS) targeting and safe adeno-associated virus (AAV) administration are critical for clinical gene therapy.
- Selecting the optimal AAV serotype is crucial for successful gene transfer into the brain and spinal cord.
Purpose of the Study:
- To compare the efficiency of lumbar intrathecal (LI) versus intracerebroventricular (ICV) AAV administration in cynomolgus macaques.
- To evaluate and compare the efficacy of AAV9 and AAVrh10 serotypes for CNS gene delivery.
Main Methods:
- Cynomolgus macaques received LI administration via catheter or ICV administration.
- Two clinically relevant AAV serotypes, AAV9 and AAVrh10, were tested.
- Transgene expression in neurons and glial cells across the brain and spinal cord was analyzed.
Main Results:
- AAV9 LI delivery resulted in consistent transgene expression in spinal cord motor neurons and widespread brain cells.
- AAV9 ICV delivery primarily achieved transgene expression within the brain.
- AAVrh10 LI delivery showed limited motor neuron targeting.
- AAV9 demonstrated efficient targeting of respiratory and skeletal muscles following cerebrospinal fluid (CSF) administration.
Conclusions:
- Lumbar intrathecal delivery of AAV9 via catheter is an effective method for whole CNS targeting in non-human primates.
- AAV9 exhibits a unique tropism for both CNS and peripheral muscles when administered into the CSF.
- This dual targeting capability of AAV9 presents significant opportunities for treating complex neurological and neuromuscular disorders.
