We will be posting a series of summaries from our 2014 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This is the third of four total updates, and the first of two in drug discovery and clinical trials.

This summary was written by Cure SMA Scientific Advisory Board member Elliot J. Andropy, Professor, Indiana University. Dr. Andropy was also the moderator for this session.

SMA Therapy Development and Clinical Research

The presentations in this session covered critical issues for SMA drug development, and specific drugs currently in development.

The first two talks addressed two critical questions for SMA drug development:

  • When is the SMN protein required—is it just during early life, or later?
  • Is restoration of SMN in motor neurons all that is needed, or is SMN also necessary in other tissues and organs?

Then three new promising opportunities for the treatment of SMA were presented: antisense oligonucleotides to correct SMN2 splicing, SMN1 gene replacement using gene transfer, and a novel muscle-enhancer.

Dr. Laurent Bogdanik, a Cure SMA-funded researcher from Jackson Laboratory (JAX) in collaboration with Dr. Cathleen Lutz, presented a new intermediate mouse model of SMA created at JAX. He described their new mouse model, called the Burgeron model, and how it was used it to test a small molecule, provided by Roche, that increases the SMN protein levels at different time points.

The group tested the drug in pre-symptomatic mice (day 10 after birth) and post-symptomatic mice (day 25 after birth). The results showed that earlier treatment was more effective, although post-symptomatic SMN restoration did confer some benefit in the Burgheron mouse model.

Next Dr. Sandra Duque, from the Cure SMA funded-Burghes lab at OSU, discussed a pig model of SMA. Using a specially-designed viral vector, they lowered SMN levels in pigs at day five after birth, mimicking key clinical features of SMA.

Importantly, when they injected therapeutic gene therapy vectors after the onset of symptoms, this had a positive impact on the progression of the disease. This is first large animal model of SMA.

Dr. Martine Barkats of INSERM and Dr. Brain Kaspar, a Cure SMA funded researcher from Nationwide Children’s Hospital, described the utility of adeno–associated viral (AAV) vectors in the treatment of SMA in the next two talks.

AAV vectors have been engineered to efficiently “infect” motor neurons with new DNA , and can be directed to express SMN in a variety of other cell types too.

Dr. Kaspar announced that his collaborator Dr. Jerry Mendell at Nationwide Children’s Hospital has initiated a clinical trial in which AAV vectors are injected into veins of infants less than 9 months of age with SMA.

With Cure SMA funding, work is also being done to advance central nervous system (CNS) administration of gene therapy, which would allow bigger and older patients to be treated. Dr. Barkats then discussed the potential importance of peripheral expression of SMN outside of the nervous system for the rescue of mouse models of SMA, when using gene therapy applications.

Dr. Yimin Hua, a Cure-SMA funded researcher from the Krainer lab at Cold Harbor Laboratory, presented experiments using antisense oligonucleotides that distribute to the central nervous system, or to the rest of the body, in severe SMA mice. His data indicated that the systemic delivery to the entire body yielded greater improvement in severe SMA mice, compared to CNS delivery alone. He is also exploring whether the chemical backbone of the oligonucelotide influences how well it works.

Dr. Darren Hwee a Cure-SMA funded researcher from Cytokinetics, reported that Tirasemtiv treatment increased muscle force, improved grip strength, grid hang time, and resistance to fatigue in intermediate and mild mouse models of SMA.

Tirasemtiv is a muscle protectant that enhances muscle function, and it is currently being tested in clinical trials in ALS patients.