Neurodegenerative Diseases

We are pursuing the discovery and development of antisense drugs for neurodegenerative diseases in which there is a large unmet need for new treatment options. Our goal is to develop antisense drugs to treat diseases with identified genetic causes. We have initiated several programs to develop drugs to treat severe neurodegenerative disease and funded three of these programs through grants. In addition, as part of our alliance with Genzyme, we have a preferred partner relationship for the development and commercialization of antisense drugs for certain neurodegenerative and rare diseases. Our most advanced neurodegenerative program is ISIS-SOD1_Rx, an antisense drug to treat amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease. In December 2009, we announced the advancement of another drug, ISIS-SMN_Rx for the treatment of SMA to our pipeline. ISIS-SMN_Rx is the first antisense drug to enter our pipeline that modulates splicing, an alternate antisense mechanism.

• ISIS-SOD1_Rx (Amyotrophic Lateral Sclerosis)
• ISIS-SMN_Rx (Spinal Muscular Atrophy)

ISIS-SOD1_Rx

ISIS-SOD1_Rx is an antisense drug that targets superoxide dismutase, or SOD1, a molecule associated with an inherited, aggressive form of ALS. The FDA granted ISIS-SOD1_Rx Orphan Drug designation for the treatment of ALS. Because antisense drugs do not cross the blood-brain barrier, a small pump administers the drug directly into the CNS infusing the drug into the cerebral spinal fluid. Clinicians call this type of administration intrathecal infusion.

Researchers reported in the Journal of Clinical Investigation that treatment with ISIS-SOD1_Rx prolonged life in rats that showed many symptoms of ALS. By delivering our drug directly to the fluid that circulates within the CNS, we and our collaborators lowered production of the mutant protein in neurons and surrounding cells.

The ALS Association and the Muscular Dystrophy Association are providing funding for ISIS-SOD1_Rx. Additionally, as part of our alliance with Genzyme, Genzyme has a right of first negotiation to license ISIS-SOD1_Rx from us. We are evaluating ISIS-SOD1_Rx in a Phase 1 study in patients with the familial form of ALS.

ISIS-SMN_Rx

ISIS-SMN_Rx is an antisense drug designed to treat SMA, a neuromuscular disorder and the leading genetic cause of infant mortality. The incidence of SMA is 1 in 6,000 to 10,000 births, and most infants born with the most severe form of SMA, Type 1, die within two years according to the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. A genetic deletion of the survival motor neuron 1, or SMN1, gene is responsible for SMA. ISIS-SMN_Rx increases the production of the protein SMN by modulating the splicing of a closely related pre-mRNA, SMN2. Normal motor function is associated with normal levels of SMN. By altering splicing to produce SMN, ISIS-SMN_Rx may compensate for the underlying genetic defect.

In 2008, we and researchers from Cold Spring Harbor published data that demonstrated the feasibility of using our antisense technology to control splicing. Our collaborative work with Cold Spring Harbor led to the discovery of ISIS-SMN_Rx. Our SMA program is part of our collaboration in neurodegenerative disease with Genzyme, pursuant to which Genzyme has a right of first negotiation to license ISIS-SMN_Rx from us.