Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.
Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). The use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS.
Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA.
Josef
J
Pleticha
Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA.
Christian
C
Jeng-Singh
Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA.
Rahaf
R
Rezek
Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA.
Manal
M
Zaibak
Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: beutler.andreas@mayo.edu.
Andreas S
AS
Beutler
D000818:Animals; D018481:Convection; D000229:Dependovirus / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007267:Injections / Q000379:methods; D008297:Male; D009437:Neuralgia / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*
Adeno-associated virus rh20; Convection-enhanced delivery; Dorsal root ganglion; Intraneural; Intrathecal; Peripheral nervous system