Research advances in gene therapy approaches for the treatment of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons that causes progressive muscle weakness, paralysis, and premature death. No effective therapy is available. Research in the motor neuron field continues to grow, and recent breakthroughs have demonstrated the possibility of completely achieving rescue in animal models of spinal muscular atrophy, a genetic motor neuron disease. With adeno-associated virus (AAV) vectors, gene transfer can be achieved with systemic non-invasive injection and minimal toxicity. In the context of this success, we review gene therapy approaches for ALS, considering what has been done and the possible future directions for effective application of the latest generation of vectors for clinical translation. We focus on recent developments in the areas of RNA/antisense-mediated silencing of specific ALS causative genes like superoxide dismutase-1 and other molecular pathogenetic targets, as well as the administration of neuroprotective factors with viral vectors. We argue that gene therapy offers new opportunities to open the path for clinical progress in treating ALS.

AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS

“…Intramuscular delivery of AAV6 encoding silencer shSOD1 RNA transduced SMN, but failed to alter disease course in the hSOD1 G93A mouse (Towne et al, 2011). Moreover, CST fibers were labeled and mixed neuron populations were transduced by direct AAV injection into the motor cortex (Hutson et al, 2011), but effective retrograde transduction of CSMN has never been achieved, even though AAV-mediated gene therapy approaches have been considered for ALS (Nizzardo et al, 2011). …”

A missense mutation in AGTPBP1 was identified in sheep with a lower motor neuron disease

“…Our finding in sheep, a large mammalian species, raises the possibility that human patients with similar etiology may also result from this gene or other genes in the same pathway of neuronal development. As there is no effective treatment available for MNDs, the identification of molecular pathogenetic targets will shed light on the development of gene therapy for this type of diseases (Nizzardo et al, 2011). Here, we reported that LMN disease originating in a Romney ram was likely caused by a mutation in a gene locus AGTPBP1 (NNA1).…”

“…MNDs are considered incurable and no effective treatment is currently available. However, the gene therapy strategy of performing gene transfer to patients by utilizing adeno-associated virus vectors is a promising therapeutic approach (Nizzardo et al, 2011). Previous evidence has shown genetic variants within 430 genes might be responsible for MND (Dion et al, 2009).…”

Current developments in gene therapy for amyotrophic lateral sclerosis

“…Published review articles, for instance Federici et al and Nizzardo et al in 2012 summarised the most promising advances at that point [11,12]. Here, we will seek to summarise and critically evaluate current developments in gene therapy targeting ALS by examining the main techniques that are being utilised, with attention to the potential for their future clinical application.…”