Gene and protein therapies utilizing VEGF for ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2–5 years. Unfortunately, the only treatment currently available is riluzole, which has a limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.

Evaluating the levels of CSF and serum factors in ALS

“…We choose common neurotrophic factors, including bFGF and VEGF, and surveyed their differences between ALS patients and control subjects. VEGF is associated with angiogenesis and has recently been shown to exert neurotrophic effects on neurons (Keifer, O'Connor, & Boulis, 2014); a similar trophic effect was also found with bFGF (Chen, Cai, Shen, Cai, & Lei, 2014). We measured increased bFGF and VEGF levels in both the CSF and serum and noted positive correlations with disease duration but negative associations with DPR.…”

Plasma derived from human umbilical cord blood: Potential cell‐additive or cell‐substitute therapeutic for neurodegenerative diseases

“…A recently published study demonstrated that microRNA‐containing exosomes derived from maternal and umbilical cord serum dramatically promote human umbilical vein endothelial cell proliferation, migration, and tube formation in vitro, highlighting the important role of exosomes in the regulation of angiogenesis during gestation. Exclusively, VEGF has been studied for potential therapeutic efficacy in animal models of ALS and its use in clinical settings has been discussed (reviewed). Nevertheless, CBP containing high levels of IL‐8 and VEGF might be a beneficial treatment for repair of the damaged blood–brain barrier and/or blood–spinal cord barrier in patients with ALS, AD, Parkinson's disease and multiple sclerosis …”

Expression of the axon‐guidance protein receptor Neuropilin 1 is increased in the spinal cord and decreased in muscle of a mouse model of amyotrophic lateral sclerosis

“…In our current analysis of transgenic SOD1 G93A mouse spinal cord and muscle tissue, we detected no significant difference in VEGF mRNA expression between mutant SOD1 G93A and wildtype animals. Previous studies have consistently shown positive effects of treatment with VEGF on motor function and survival in ALS animal or in vitro models (Dewil et al, 2007;Dodge et al, 2010;Keifer, O'Connor, & Boulis, 2014;Lemmens et al, 2007;Li, Xu, Luo, Gozal, & Liu, 2003;Pronto-Laborinho et al, 2014;Storkebaum et al, 2005;Zheng, Nennesmo, Fadeel, & Henter, 2004). Increased Nrp1 expression in spinal cord tissue might therefore represent a regulatory mechanism to enhance VEGF effects.…”