Affiliations: [a] Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| [b] Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| [c] BioBlast Pharma Ltd., Tel Aviv, Israel
Correspondence:
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Correspondence to: Hagar Greif, BioBlast Pharma Ltd., 37 Menachem Begin Road, Tel Aviv, 6522042, Israel. Tel.: +972 240 9060; E-mail: Hagar.Greif@bioblastpharma.com and Christian L. Lorson, Department of Veterinary Pathobiology, Christopher S. Bond Life Sciences Center, 1201 Rollins Road, Room 471G, University of Missouri, Columbia, MO 65211, USA. Tel.: +1 573 884 2219; Fax: +1 573 884 9395; E-mail: lorsonc@missouri.edu.
Abstract: Background:Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides. Objective:The objective was to determine the efficacy of the macrolide Azithromycin (AZM), an FDA approved read-through-inducing compound, in the well-established severe mouse model of SMA. Methods:Initially, dosing regimen following ICV administrations of AZM at different post-natal days and concentrations was determined by their impact on SMN levels in disease-relevant tissues. Selected dose was then tested for phenotypic parameters changes as compared to the appropriate controls and in conjugation to another therapy. Results:AZM increases SMN protein in disease relevant tissues, however, this did not translate into similar improvements in the SMA phenotype in a severe mouse model of SMA. Co-administration of AZM and a previously developed antisense oligonucleotide that increases SMN2 splicing, resulted in an improvement in the SMA phenotype beyond either AZM or ASO alone, including a highly significant extension in survival with improvement in body weight and movement. Conclusions:It is important to explore various approaches for SMA therapeutics, hence compounds that specifically induce SMNΔ7 read-through, without having prohibitive toxicity, may provide an alternative platform for a combinatorial treatment. Here we established that AZM activity at a low dose can increase SMN protein in disease-relevant animal model and can impact disease severity.
