AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials

Abstract

Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway. Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed. Expert opinion: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction.

Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

“…This modality of vector delivery has also been the first in humans for a CNS application (Janson et al, 2002) and remains the norm in most clinical programs so far (see Table 1). For motor neuron disorders, multilevel injections in the spinal cord parenchyma have been successful to deliver therapeutic agents in amyotrophic lateral sclerosis (ALS) mouse models (Azzouz et al, 2000;Franz et al, 2009;Hardcastle et al, 2018). Translation to larger mammals and humans has been challenging due to the risky surgical intervention and the focal nature of the resulting transgene expression.…”

BDNF impact on synaptic dynamics: extra or intracellular long-term release differently regulates cultured hippocampal synapses

“…Previous attempts to use intravenous or intrathecal delivery of exogenous BDNF for the treatment of neurodegenerative diseases have failed [96,97]. Thus, current therapeutic approaches have been redirected to delivery of mesenchymal cells overexpressing BDNF [98] or to viral-mediated gene therapy in the CNS parenchima [99]. In this framework we perceived as relevant to provide a detailed analysis of the differential synaptic outcomes of BDNF treatments through bath application vs genetic delivery in cultured neuronal networks.…”

Accuracy of image-guided percutaneous injection into a phantom spinal cord utilizing flat panel detector CT with MR fusion and integrated navigational software

“…With this technology, we have shown needle positioning with tip placement accuracy within 2.1 mm of a pre-determined spinal cord target. Potential translational applications of this technology are numerous and include intramedullary delivery of stem cells or other therapeutics for patients with spinal cord injury1 28 and neurodegenerative diseases of the spinal cord such as ALS and spinal muscular atrophy,2 minimally invasive spinal cord or epidural biopsy, and direct delivery of chemotherapeutics for spinal cord tumors 4. This technology could potentially be modified for minimally invasive placement of drainage catheters in syringomyelia.…”