Antisense oligonucleotide treatment delivered to ALS patients in Phase 1 safety study: Implications for HD

In a small percentage of patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, a mutation in the protein called SOD1 has been found to cause a familial or inherited form of the disease.  This genetic link to ALS makes individuals that bear this mutation, ideal candidates to test exploratory new therapies that silence the SOD1 gene.  With that in mind, researchers from Washington University in St. Louis and Massachusetts General Hospital, with support from Isis Pharmaceuticals, set out to test an experimental antisense oliognucleotide (ASO) that selectively lowers the mutant SOD1 gene in humans.

The goal of this clinical study was to assess the safety and tolerability of a single dose of the Isis ASO (ISIS-333611) that lowers the mutant form of the protein SOD1.  Twenty one ALS patients were enrolled sequentially in four different groups representing four single, yet escalating doses of the Isis ASO.  Each group was comprised of 6 ALS patients and 2 placebo controls.  While most patients (84%) reported some sort of adverse event such as headache or back pain, it was concluded the discomfort was due to the infusion procedure and not the study drug.  They found that none of the study participants experienced any serious safety or tolerability issues related to the test ASO. 

This significance of this trial is that it is the first clinical study that administered an ASO using intrathecal (spinal cord) delivery.  It is very likely the first trial using the Isis/Roche ASO to lower huntingtin will be delivered in the same way to HD patients. 

The encouraging results from this study will not only assist researchers in the design of the next ALS ASO clinical study, but will provide valuable insight into the conduct of the huntingtin ASO trial that is being planned.  Timothy Miller, MD, PhD, the lead author of this study, was quoted as saying, “These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders.  These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”



Timothy M Miller, Alan Pestronk, William David, Jeffrey Rothstein, Ericka Simpson, Stanley H Appel, Patricia L Andres, Katy Mahoney, Peggy Allred, Katie Alexander, Lyle W Ostrow, David Schoenfeld, Eric A Macklin, Daniel A Norris, Georgios Manousakis, Matthew Crisp, Richard Smith, C Frank Bennett, Kathie M Bishop, Merit E Cudkowicz.  An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurology, 435-442,  (2013).