Cure SMA Awards $150,000 to Drs. Hua and Krainer at CSHL to Investigate Antisense Oligonucleotides for Spinal Muscular Atrophy

Originally published on August 8, 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 fourth drug discovery project funded by Cure SMA in 2013 with a total investment of $550,000.

This program will systematically assess the effect of backbone chemistry on the therapeutic efficacy of Antisense Oligonucleotides (ASO) that target the ISS-N1 region of the SMN2 RNA. ASOs that bind to the ISS-N1 region will be compared.  This is the binding region of the drug ISIS-SMNRx that is currently being tested by Isis Pharmaceuticals in SMA clinical trials.  This funding is being awarded to Dr. Yimin Hua in the laboratory of Dr. Adrian Krainer at Cold Spring Harbor Laboratory.  Both scientists are long-term collaborators with Isis Pharmaceuticals and actively participated in the pre-clinical development and characterization of the mechanism of action of ISIS-SMNRx.

Comparison of efficacy mechanisms of MOE & PMO antisense splicing therapy in SMA mice

Objective: The project goal is to compare the ISS-N1 antisense oligonucleotides using two alternate backbone chemistries called MOE and Morpholino (PMO).  Both chemistries have shown great promise in treating SMA by correcting SMN2 splicing.  In this project, the team will systematically explore parameters that influence the efficacy of each type of ASO.
Research Strategy: The researchers will use a severe type I SMA mouse model to compare the therapeutic effects of antisense oligonucleotides with two types of chemical backbones, delivered either to the central nervous system or under the skin. They will then perform detailed pharmacological studies to compare the distribution and efficacy in different tissues and cell types. This project will provide important information for further developing the antisense oligonucleotide drug, ISIS-SMNRx, an antisense oligonucleotide drug candidate that is currently in clinical trials by Isis Pharmaceuticals. This project may also help understanding of which tissues or cells are most important in SMA pathogenesis in this mouse model.

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 (ASO) 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 RNA made from the SMN2 gene to increase the production of functional 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 express more full-length SMN protein, rather than truncated, low-functioning protein.

How can Backbone Chemistry Influence Effectiveness?

A factor that influences the effectiveness of an ASO is the backbone chemistry used to hold the nucleotides together. The different ASO chemistry can influence many factors, including: 1) how the ASO distributes throughout the body; 2) the length of time the ASO persists in a given tissue; 3) the efficiency of ASO uptake into cells; 4) how strongly a particular ASO binds to the target RNA; and 4) the likelihood of non-specific interactions with other RNAs.

“As a Research Investigator in my lab at Cold Spring Harbor Laboratory, and as part of our long-standing collaboration with Isis, Dr. Hua has been doing pioneering work towards the development and characterization of the mode of action of ISIS-SMNRx. I am grateful for the support from Cure SMA, which will allow Dr. Hua to study key aspects of ASO efficacy in SMA mouse models, with relevance to the clinic,” said Dr. Adrian Krainer, Ph.D.,  Professor at Cold Spring Harbor Laboratory.
“ASO10-27 (ISIS-SMNRx) and its longer derivatives, which restore SMN expression through correction of SMN2 splicing, hold great promise to treat spinal muscular atrophy. ASOs must be chemically modified to enhance their stability and facilitate their binding to the target RNA. ASOs with different chemical modifications have been tested in various SMA mouse models; two types of modifications, MOE and morpholino, showed striking improvement including long-term survival. However, there were apparent differences among various studies, in terms of optimal ASO dose and sites of delivery. We will conduct a comprehensive side-by-side comparison of MOE and morpholino ASOs in a severe mouse model, and study the mechanisms underlying any observed differences in ASO potency and efficacy,” said Yimin Hua, Ph.D., Research Investigator at Cold Spring Harbor Laboratory.
“We have a long term collaboration with Drs. Adrian Krainer and Yimin Hua to identify an antisense drug to treat spinal muscular atrophy. This has been a very productive collaboration resulting in the identification of ISIS-SMNRX, which is currently in clinical trials.  We would be delighted to continue to work with Dr. Hua to investigate the mechanistic differences between the different olignucleotide chemistries.  Dr. Hua has a strong track record of successfully completing projects and making important contributions to our understanding of SMA and antisense drugs,” said Dr. C. Frank Bennett, Ph.D., Senior Vice President of Research, Isis Pharmaceuticals.

About Cold Spring Harbor Laboratory

Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL’s multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center. Tens of thousands more benefit from the research, reviews, and ideas published in journals and books distributed internationally by CSHL Press. The Laboratory’s education arm also includes a graduate school and programs for middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island. For more information, visit

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