Originally published on May 2, 2013.

Cure SMA is dedicated to creating a treatment and cure for spinal muscular atrophy by funding and advancing a comprehensive research program, including drug discovery programs to make practical new therapies.  This is the third of four drug discovery project awarded by Cure SMA in 2013 with a total investment of $550,000. This program will assess the therapeutic potential of second-generation Antisense Oligonucleotides (ASO) sequences for SMA. This funding is being awarded to Co-Principal Investigators Dr. Arthur Burghes at Ohio State University and Dr. Christian Lorson at University of Missouri.

Program Description:

New Morpholino Antisense Oligonucleotides for the Treatment of SMA.

Objective: Antisense oligonucleotides (ASOs) targeted to the ISS-N1 region have been shown to be effective in mice and are now being tested in the current clinical trials conducted by Isis Pharmaceuticals. The major goal of this new program is to explore the therapeutic potential of two new sequences, which are located in different regions of the SMN2 gene. Importantly, the possibility exists to use these different ASOs in combination. The ASOs in this project will be generated using a different morpholino backbone chemistry.

Research Strategy: First, the Burghes and Lorson groups will determine the optimal nucleic acid sequence. They will then establish the best dose of the optimized ASOs to provide maximal rescue in the severe Delta7 mouse model of SMA, developed by Dr. Burghes. Knowing this information in mice will help design subsequent studies in primates to assess whether these ASOs reach the correct tissues including motor neurons, when delivered into the cerebral spinal fluid (CSF) in larger animals. Dr. Ravindra Singh at Iowa State University will be collaborating on the project.

How Does the ASO Approach for SMA Work?

This therapeutic approach for SMA involves the use of small pieces of genetic material, called oligonucleotides, to increase the production of a missing protein. The methodology is often called Antisense Oligonucleotide technology. In SMA, the SMN protein is reduced due to the loss of the SMN1 gene. A second closely related back-up gene called SMN2 exists that normally produces a truncated and low-functioning form of SMN protein. 

ASOs can be designed that bind to specific regions of the SMN2 gene to drive the production of SMN protein. The ASO prevents the exclusion of exon 7, correcting the known splicing defect in SMN2. This allows the SMN2 back-up gene to produce full length SMN protein, rather than truncated, low-functioning protein. 

“We are very grateful to Cure SMA for funding our ASO project as we hope we can continue to develop therapeutics that target an additional genetic element within SMN2. SMA is a very complex disease and it is possible that more therapeutic options will be required to effectively combat this disease,” stated Chris Lorson, Ph.D., Professor at University of Missouri.

“There are now a series of exciting therapies for induction of SMN from the back-up gene SMN2, with the antisense oligonucleotides being one.   In essence, the best way to increase SMN protein from SMN2 remains a critical issue, and this will be investigated in this new project,” stated Arthur Burghes Ph.D., Professor at Ohio State University.

This current Cure SMA award is for one year with the goal of optimizing and assessing the therapeutic potential of novel ASO sequences from the SMN2 back-up gene. Subsequent funding to advance these ASOs towards an Investigational New Drug application to the FDA will be evaluated by our TAC through our planned 2014 Request for Proposals in Preclinical SMA Drug Development.

A portion of this new research program is being generously funded by Stop SMA.

Stop SMA was created to raise awareness and funding for research to treat and end SMA. Inspired by the diagnosis of Evie Horton and Reese McDonald, family and friends have joined together to advocate for all families facing SMA and change the prognosis of the disease forever.  Cure SMA is appreciative of the ongoing partnership with the Horton family and Stop SMA and gratefully acknowledges their contribution to the advancement of new SMA therapies.