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

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Families of 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 Families of 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.

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.

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 Families of 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

The SMA Drug Pipeline
There are now 15 new SMA drug programs in development, including 3 in clinical trials. This pipeline has expanded from just 4 programs 5 years ago. Families of SMA has funded over half of all the ongoing drug programs for SMA. The FSMA research approach funds programs at early stages, and then partners with companies to take them through clinical trials. Supporting multiple programs gives different approaches for a SMA therapy, which increases the chances of success and accelerates the timeline to a treatment and cure.

About Families of Spinal Muscular Atrophy
Families of SMA is the world’s leader focused on funding SMA research to develop a treatment and cure for the disease. The successful results and progress that the organization has delivered, from basic research to drug discovery to clinical trials, provide real hope for families and patients impacted by the disease. The charity has invested over $55 million in research and has been involved in funding half of all the ongoing novel drug programs for SMA. Families of SMA is a nonprofit 501(c)3 organization, with 31 Chapters and 90,000 members and supporters throughout the United States. The organization’s work has produced major discoveries, including identification of the underlying cause and a back-up gene for the disease, which provides a clearly defined target for disease altering therapies. The organization is also dedicated to supporting SMA families through networking, information and services and to improving care for all SMA patients. http://www.curesma.org

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 http://www.cshl.edu.

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