Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons

Abstract

Therapeutic gene delivery to the whole spinal cord is a major challenge for the treatment of motor neuron (MN) diseases. Systemic administration of viral gene vectors would provide an optimal means for the long-term delivery of therapeutic molecules from blood to the spinal cord but this approach is hindered by the presence of the blood-brain barrier (BBB). Here, we describe the first successful study of MN transduction in adult animals following intravenous (i.v.) delivery of self-complementary (sc) AAV9 vectors (up to 28% in mice). Intravenous MN transduction was achieved in adults without pharmacological disruption of the BBB and transgene expression lasted at least 5 months. Importantly, this finding was successfully translated to large animals, with the demonstration of an efficient systemic scAAV9 gene delivery to the neonate and adult cat spinal cord. This new and noninvasive procedure raises the hope of whole spinal cord correction of MN diseases and may lead to the development of new gene therapy protocols in patients.

Repair of pre-mRNA splicing

“…newborn mice, cats or non-human primates. 109,154,155 In particular, two groups have recently reported a significant clinical amelioration in SMA mice after scAAV9-or scAAV8-mediated introduction of a SMN cDNA. 109,110 Future work will have to reveal which type of gene therapy is most efficient in a human clinical setting, a gene replacement approach as used in these two studies or one of the splicing correction strategies described above.…”

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

“…Towards developing viral vector-mediated delivery of the QBP1 transgene as a therapy, several issues, such as control of gene expression and delivery of the virus throughout the patient brain, are anticipated to be solved. Using a bloodbrain barrier (BBB)-permeable virus vector, such as AAV9 [36], may help to overcome the brain delivery issue. For administration of the QBP1 peptide, we utilized PTDs to enable the intracellular delivery of QBP1, which are peptide sequences that are capable of penetrating the cell membrane and entering cells, and can thereby deliver covalently-bound cargo molecules into cells [37,38].…”

Contributions from scientific research to the risk assessment of GMOs. Lessons learned from a symposium held in Brussels, Belgium, 21–22 October 2010

“…The delivery method should also be evaluated as it may alter the vectors capacity to disseminate into different tissues and, if cells of excretory systems are transduced, potentially change the shedding route of the recombinant viruses. For example, an altered biodistribution has been observed in a study where rAAV vectors have been delivered to the brain through several modes of administration (Duque et al, 2009;Hadaczek et al, 2009).…”