Introduction

We propose to develop a drug product to treat all forms of ALS by targeting an important pathogenic pathway, miR-129-1 that is up-regulated in both familial and sporadic ALS patients, in human and SOD1^G93A mice (A-B). Antisense technology is entering a phase of clinical successes and we believe that our strategy can provide clinically meaningful benefit to patients that have no therapeutic hope. To date, current approved treatments for ALS, which at best guarantee a span life extension of 3 months, are riluzole (Li et al., Plos One 2013) and edaravone (Ito et al, Exp Neurol, 2008) .

Technical features

Our proposed miR-129-1 PMO therapeutic strategy outperformed when compared with these ALS approved molecules. Our patented a miR-129-1 modulation strategy with a Morpholino Antisense Oligonucleotide (ASO-PMO) and demonstrated in vivo that it recovers the expression of its target protein HuD, allowing for a 12.5% ​​increase in survival and an improvement neuromuscular performance of SOD1^G93A  mice, a genetic model of ALS, treated in the pre-symptomatic phase. To improve miR-129-1 PMO therapeutic efficacy, better delivery to target tissue is needed: based on our experimental data from another study on motor neuron disease, an arginine-rich peptide conjugated with PMO (CPP-PMO) shows an increased efficacy in vivo. In addition, the mouse model TDP43 can be used to demonstrate a more general efficacy of the product, before proceeding with toxicological and pharmacokinetic evaluation in the preclinical setting. In addition, the mouse model TDP43 can be used to demonstrate a more general efficacy of the product, before proceeding with toxicological and pharmacokinetic evaluation in the preclinical setting.

Possible Applications

• Familial amyotrophic lateral sclerosis, Sporadic amyotrophic lateral sclerosis, Alzheimer Disease, Epilepsy, Fragile X syndrome, Tubero sclerosis complex and Cornea pathologies.

Advantages

• Targeting miRNA allows modulation of a large number of target genes;
• PMO works as a steric-blocker, a more effective strategy when the target is a miRNA;
• PMO is superior to small molecules for improved target affinity;
• PMO fulfills important criteria of solubility, stability, binding affinity, in vitro and in vivo efficacy and in vivo toxicity if compared to other chemistries;
• PMO has low risk in terms of toxicity, off target effects and immune response stimulation.