Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy

Abstract

Different adeno-associated virus (AAV) serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF) could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons) and in the spinal cord (up to one-third of α-motor neurons). As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I) favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I–treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases.

A Role for Insulin in Diabetic Neuropathy

“…Additional studies of IGF have also demonstrated a role for impaired IGF signaling in motor neurons in diabetic neuropathy (Simon et al, 2015; Rauskolb et al, 2017). Viral delivery of IGF1 to models of diabetic neuropathy also revealed positive actions of IGF1 perhaps through vascular endothelial growth factor expression (VEGF), and signaling via Akt/PI3K pathways in sensory and motor nerves (Homs et al, 2014). …”

AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy

“…Recombinant AAVrh.10 shows promise for gene therapy. It stably-transduces neurons and to a lesser extent oligodendrocytes, after intracranial or intrathecal administration, demonstrating capacity to revert different centraland peripheral-nervous system pathologies in mouse models such as late-infantile neuronal ceroid lipofuscinosis, 8 metachromatic leukodystrophy, 9 diabetic neuropathy, 10 and amyotrophic lateral sclerosis 11 among other diseases. Recently rAAVrh.10 was approved for two clinical trials to treat late-infantile neuronal lipofuscinosis (NCT01161576) and Sanfilippo Type A syndrome.…”

Peripheral pain is enhanced by insulin‐like growth factor 1 and its receptors in a mouse model of type 2 diabetes mellitus

“…Insulin‐like growth factor 1 is a neurotrophic factor widely expressed in the body. It has a proven positive effect on diabetic peripheral neuropathy and, as such, IGF1 is involved as a neurotrophic factor in the treatment of diabetic neuropathy . Nevertheless, it has been reported that IGF1 may lead to hyperalgesia.…”