New Therapeutic Avenues for Spinal Muscular Atrophy in Development by ISIS Pharmaceuticals, Inc.

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ISIS Antisense Therapy Program for Spinal Muscular Atrophy 2010 Project Update Isis Pharmaceuticals, Inc. (ISIS) is a biotechnology company in San Diego, CA, that focuses on RNA targeting therapeutics. In December 2009, ISIS announced it had added a Spinal Muscular Atrophy (SMA) Drug to its development pipeline. This drug is called ISIS-SMNRx and is specifically designed to potentially treat SMA through the correction of SMN2 RNA splicing, the low-functioning back-up gene found in all SMA patients. The first animal model results were published online in the journal Genes and Development this week. Using this approach, ISIS hopes to provide therapeutic benefit to patients with SMA.

...we have made significant progress in identifying a drug development candidate (for SMA) and toward conducting preclinical studies to access therapeutic potential. We are committed to advancing this program toward the clinic. Dr. C. Frank Bennett, Ph.D

Families of Spinal Muscular Atrophy (FSMA) - Elk Grove Village

ISIS Antisense Therapy Program for Spinal Muscular Atrophy 2010 Project Update:

Isis Pharmaceuticals, Inc. (ISIS) is a biotechnology company in San Diego, CA, that focuses on RNA targeting therapeutics. In December 2009, ISIS announced it had added a Spinal Muscular Atrophy (SMA) Drug to its development pipeline. This drug is called ISIS-SMNRx and is specifically designed to potentially treat SMA through the correction of SMN2 RNA splicing, the low-functioning back-up gene found in all SMA patients. The first animal model results were published online in the journal Genes and Development this week. Scientists at Cold Spring Harbor Laboratory (CSHL) and Isis Pharmaceuticals have substantially reduced and delayed the onset of symptoms in a mouse model of Type III SMA, a relatively mild form of the disease, by injecting the antisense oligonucleotide (ASO) into their spinal cords.

RNA is the molecule that translates information stored in our genes into proteins. By targeting RNA, the amount of disease causing proteins, such as the SMN protein that is chronically depleted in SMA, can be modulated. The primary technology used to target disease RNA is called antisense technology, where antisense oligonucleotides (ASOs) are used as the drug substance. Antisense oligonucleotides are chemically synthesized pieces of nucleic acid designed to bind to RNA in a very selective manner and thereby regulate the function of the RNA. This results in either increased or decreased amounts of the protein produced from the targeted RNA.

In the case of SMA, the antisense drug has been shown to increase the production of the SMN protein, by targeting the RNA of the SMN2 gene. The SMN2 gene is the closely related back-up gene to the SMN1 gene that is typically deleted in SMA patients. It normally produces a truncated and low-functioning form of SMN protein. The ISIS drug is designed to bind the SMN2 RNA, driving the production of full-length, functional SMN protein, by altering the RNA splicing of the SMN2 gene. This type of drug is called a splicing modulator.

Using this approach, ISIS hopes to provide therapeutic benefit to patients with SMA.

ISIS Project Timeline and Path Forward:

Dr. C. Frank Bennett, Ph.D., Senior Vice President, Research, ISIS Pharmaceuticals, states, “Our antisense drug for the treatment of SMA will be administered by an injection into the fluid that surrounds the spinal cord and brain by a process called intrathecal injection, which is used to delivery other types of drugs into the central nervous system. In animal studies, ISIS-SMNRx was shown to markedly increase the production of SMN protein in motor neurons, increase muscle strength and prolong survival in models of SMA. This drug is currently in pre-clinical development. Studies evaluating the safety and distribution of the drug in animals will begin later this year. These studies are necessary to support studies in SMA patients and will take about 1 year to complete.”

Dr. Bennett continues, "SMA is the leading genetic cause of infant mortality and has limited treatment options for patients. With Dr. Krainer's lab at Cold Spring Harbor Laboratory, we have made significant progress in identifying a drug development candidate (for SMA) and toward conducting early preclinical studies to access its therapeutic potential. We are committed to advancing this program toward the clinic.”
The first in human studies (clinical trials) will primarily be designed to test the safety of the drug in SMA patients and will be of relatively short duration. Positive data from first in human studies will allow for longer duration dosing of the drug and the assessment of possible benefit in children with SMA.
Dr. C. Frank Bennett, Ph.D. was a panelist at the 2010 Families of SMA Annual Conference in Santa Clara, CA.

Please click here to read the Cold Spring Harbor Laboratory paper abstract.

Please click here to learn more about this approach on the Families of SMA (FSMA) website.

In order to commercially develop their therapeutic candidate for SMA, Isis Pharmaceuticals, Inc. exclusively licensed certain intellectual property from the University of Massachusetts. Families of SMA funded in part the early research for the foresighted program that led to this intellectual property with three grant awards of over $500,000 to Dr. Rivindra Singh and his colleagues between 2003 and 2006. The work was done in collaboration with Dr. Elliott Androphy at the University of Massachusetts.

“This program is a perfect illustration of how funding basic research often leads to new therapeutic avenues to treat SMA. This idea is one of the main tenets of the FSMA research strategy,” says Jill Jarekci, Ph.D., Research Director of FSMA.

About ISIS Pharmaceuticals:

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 22 drugs in development. Isis' drug development programs are focused on treating cardiovascular, metabolic, and severe neurodegenerative diseases and cancer. Isis' partners are developing antisense drugs invented by Isis to treat a wide variety of diseases. Isis and Alnylam Pharmaceuticals are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development and commercialization of microRNA therapeutics. Isis also has made significant innovations beyond human therapeutics resulting in products that other companies, including Abbott, are commercializing. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of approximately 1,600 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.

About Families of SMA:
FSMA is dedicated to creating a treatment and cure for SMA by: Funding and advancing a comprehensive research program; Supporting SMA families through networking, information and services; Improving care for all SMA patients; Educating health professionals and the public about SMA; Enlisting government support a; Embracing all touched by SMA in a caring community.
At Families of SMA, expert and independent prioritization and oversight of research projects is critical. This approach ensures that FSMA funds only the most promising research, and that the funded projects are run in a professional and efficient manner under the guidance of world-class experts. http://www.curesma.org
Contact Information:
Families of SMA
925 Busse Road
Elk Grove Village, IL 60007
Phone (800) 886-1762
Fax (847) 367-7623

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