The 19th International SMA Researcher Meeting has been recently held by Cure SMA at Kansas City, Missouri (June 18-20, 2015). Summaries with the most relevant developments and findings presented at the meeting are currently being made available.
SMA (spinal muscular atrophy) is a rare, devastating motor neuron disease and one of the leading genetic causes of pediatric mortality, occurring in approximately 1 in every 6,000 to 10,000 newborns. It is characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in muscle weakness, atrophy, paralysis and eventually death. SMA is the result of a mutation or deletion in a gene called survival of motor neuron 1 (SMN1) that results in low levels of the SMN protein.
Acording to a news release, the last session of the meeting comprised eight talks on drug discovery for SMA. The first four presentations were centered on drug programs at an early stage of development, whereas the last four referred to drugs that are currently being tested in human clinical trials in healthy volunteers or already in SMA patients. Overall, 18 drug programs compose the SMA drug pipeline, and seven of these are being evaluated in clinical trials.
Different drug strategies with the goal of increasing SMN protein levels were presented in the first four talks. The SMN protein has two identical variants – SMN1 and SMN2. SMN2 is mainly produced as an unstable and shortened version of the SMN protein due to a single nucleotide difference in the exon 7 of the gene, and therefore cannot compensate for SMN1 loss. Only around 10% of the SMN2 proteins produced are full-length and are an important determinant of disease severity. It is thought that an increase in the generation of SMN2 full-length RNA could be a therapeutic strategy for SMA.
The first talk, by BioBlast Pharma, focused on re-purposing a drug approved by the FDA (BBrm02, a formulation of azithromycin) to induce the SMN2 short form of the SMA protein to become more stable and functional. The second talk discussed the research program at Calibr, which found new molecules able to induce SMN2 expression or transcription (process through which DNA is copied into RNA; the first step of gene expression). These molecules are currently being optimized and evaluated in SMA mouse models.
The third talk was delivered by RaNA Therapeutics and focused on preliminary data of an antisense oligonucleotide able to induce SMN2 transcription ultimately leading to the production of a more functional protein. Finally, the fourth talk, given by Dr. Lorson’s group from the University of Missouri, showed that an antisense oligonucleotide could increase exon 7 inclusion in SMN2 leading to the generation of full-length functional SMN protein.
The last four talks focused on results from clinical trials. The first presentation by Dr. Claudia Chiriboga from Columbia University focused on the importance of electrical circuitry anomalies in SMA patients who are able to walk (ambulatory). The team is testing a drug called Dalfampridine-ER, a drug originally designed for the treatment of multiple sclerosis; however, up to now no positive effects on motor function were observed. The second presentation was given by ISIS Pharmaceuticals where promising data from their Phase 2 clinical trials on an antisense oligonucleotide drug (ISIS-SMNRx) in infants and children with SMA was shown.
Drs. Kaspar and Mendell presented data on ChariSMA, a clinical trial sponsored by Avexis Pharmaceutical to test an SMN gene therapy in infants with SMA. The results presented on this third talk are so far promising, with none of the infants requiring permanent ventilation. Data on a gene therapy program for adults was also presented.
Finally, the last presentation of the session was given by Roche Pharmaceuticals and focused on a drug named RG7800 that can correct the error in exon 7 in the SMN2 gene. RG7800 has been proven safe and well-tolerated in healthy adult volunteers. The drug was being tested in adult and pediatric SMA patients in a phase 1b/2a study, however, the trial was interrupted due to some recent data on toxicology in monkeys.