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NEALS SOD1 Research is First Antisense Oligonucleotide Trial for a Central Nervous System Disorder

March 29, 2013

Antisense Oligonucleotides May be Feasible Therapeutic Strategy in ALS

March 29, 2013 Boston, MA: Published online today in Lancet Neurology, an SOD1-related familial ALS trial under the direction of NEALS researchers Timothy Miller, MD, PhD (Washington University School of Medicine) and Merit Cudkowicz (Massachusetts General Hospital) indicates that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy in treating ALS.  Mutations in SOD-1 cause 13% of familial ALS cases.
The placebo controlled, double-blind, randomized, dose escalation Phase I clinical trial sought to evaluate safety, tolerability, and pharmacokinetics of ISIS 333611, an antisense oligonucleotide against SOD1.  Participants with ALS caused by mutations in SOD1 were enrolled. ISIS 333611 was well-tolerated.  There were no safety concerns.  ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight subjects with SOD1 mutation (randomized 6 drug: 2 placebo/cohort).  Participants could enroll in more than one cohort.  The four consecutive dose cohorts were 0.15 mg, 0.5 mg, 1.5 mg, and 3 mg.  Pharmacokinetic levels were consistent with levels predicted from preclinical studies.  

Supported by Isis Pharmaceuticals, the Muscular Dystrophy Association, and the ALS Association, the Isis trial is the first time antisense oligonucleotides were delivered directly to the cerebrospinal fluid (CSF) of patients with SOD1 ALS.  It was also the first antisense oligonucleotide trial for a central nervous system disorder. The concept of “turning off” SOD1 in patients with this mutation led to the groundbreaking Phase I trial.  “What we developed is a way to turn off harmful genes, erase them essentially by deleting a small part of the RNA which then no longer makes this abnormal protein,” Miller states.  This approach will also likely be applicable to other diseases of the central nervous system.  

The Phase I trial took place at four NEALS clinical research sites: Washington University in St. Louis, Massachusetts General Hospital, Johns Hopkins University, and Methodist Neurological Institute.  Study Coordination and Data Management was led by the MGH Neurological Clinical Research Institute (NCRI). A total of 21 participants were enrolled in the trial.  Further development of SOD1 antisense oligos for SOD1 familial ALS is ongoing.   

About the Northeast ALS Consortium (NEALS)
The Northeast ALS Consortium (NEALS) is an international, independent, non-profit group of researchers who collaboratively conduct clinical research in Amyotrophic Lateral Sclerosis (ALS) and other motor neuron diseases. Their mission is to translate scientific advances into new treatments for people with ALS and motor neuron disease as rapidly as possible.  NEALS has over 100 member sites in the United States, Canada, Ireland, and Israel.

About the Neurological Clinical Research Insitute (NCRI) at Massachusetts General Hospital  
The Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital accelerates translational research in neurological disorders through initiating and testing novel therapies.  The NCRI has an extensive history in leading clinical research to find new treatments for neurological diseases including Amyotrophic Lateral Sclerosis (ALS), myasthenia gravis, diabetic neuropathy, stroke, multiple sclerosis, Parkinson's disease, and Huntington's disease.

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