Systemic IGF-1 gene delivery by rAAV9 improves spontaneous autoimmune peripheral polyneuropathy (SAPP)

Abstract

Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a mouse model of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in non-obese diabetic (NOD) mice null for costimulatory molecule, B7-2 gene (B7-2−/−). SAPP is a chronic progressive and multifocal inflammatory and demyelinating polyneuropathy of spontaneous onset with secondary axonal degeneration. Insulin-like growth factor 1(IGF-1) is a pleiotropic factor with neuroprotective, regenerative, and anti-inflammatory effects with extensive experience in its preclinical and clinical use. Systemic delivery of recombinant adeno-associated virus serotype 9 (rAAV9) provides robust and widespread gene transfer to central and peripheral nervous systems making it suitable for gene delivery in neurological diseases. A significant proportion of patients with inflammatory neuropathies like CIDP do not respond to current clinical therapies and there is a need for new treatments. In this study, we examined the efficacy IGF-1 gene therapy by systemic delivery with rAAV9 in SAPP model. The rAAV9 construct also contained a reporter gene to monitor the surrogate expression of IGF-1. We found significant improvement in neuropathic disease after systemic delivery of rAAV9/IGF-1 gene at presymptomatic and symptomatic stages of SAPP model. These findings support that IGF-1 treatment (including gene therapy) is a viable therapeutic option in immune neuropathies such as CIDP.

Elimination of activating Fcγ receptors in spontaneous autoimmune peripheral polyneuropathy model protects from neuropathic disease

“…Female B7-2-null NOD mice (SAPP model) is considered the most representative model to study T-cell mediated inflammatory demyelinating nerve injury. We have characterized the clinical and pathological neuropathy temporally in these animals [16, 18]. The spontaneous inflammatory neuropathy starts in these animals around 20 weeks of age and the disease peaks around 32–35 weeks of age.…”

“…Each session consisted of three trials. The time that the mice stayed on the rod until falling was recorded, as described[16].…”

L-carnitine ameliorates peripheral neuropathy in diabetic mice with a corresponding increase in insulin‑like growth factor‑1 level

“…The beneficial effects of insulin, C-peptide and IGF-1 on neuropathy have been described, particularly for the treatment of diabetic polyneuropathy (48)(49)(50). Insulin is regarded as a nerve promotion factor that upregulates and stabilizes neuron filaments as well as tubulin in a dose-dependent manner.…”

“…In STZ-induced rats, local unilateral administration of insulin to the sciatic nerve resulted in an increased number of small myelinated fibers and prevented slow nerve conduction in the treated nerve (26). Similarly, IGF-1, which is homologous to insulin and has partial common receptor affinity, can activate post-receptor signaling in neurons to ameliorate diabetic neuropathy (50). Binding of insulin/IGF-I to insulin receptor or IGF-I receptor activates autophosphorylation of the receptor and causes phosphorylation of several intracellular substrate proteins.…”

Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke

“…52 Additional neurological disorders associated with stroke are also influenced by IGF-1. Chronic fatigue and sleep dysfunction are commonly observed in patients following stroke 53 Studies in humans and animal models have shown that IGF-1 promotes a healthy sleep cycle, and is inversely associated with chronic fatigue (as reviewed by Chennaoui et al 54 ) Moreover, IGF-1 reduces neuropathic pain across several preclinical models, [55][56][57] suggesting IGF-1 may be advantageous for reducing post-stroke pain as well. This association has yet to be tested clinically or pre-clinically.…”