Patient with inherited ALS taking part in clinical trial of experimental drug. (Mike Worful, Washington University in St. Louis)
26 July 2018. An experimental drug designed to silence a protein associated with inherited forms of amyotrophic lateral sclerosis, or ALS, is shown in tests with lab rodents to extend survival and reverse some neuromuscular damage. Findings from an academic-industry team funded in part by National Institutes of Health and led by researchers at Washington University in St. Louis appear in the 16 July issue of the Journal of Clinical Investigation.
ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder where neurons or nerve cells controlling muscles in the body begin to waste away, and can no longer send or receive signals from the brain or spinal cord. As the nerve cells stop functioning, the muscles in the limbs, and later speech and breathing muscles, begin weakening and eventually stop functioning. Most people with the disease die of respiratory failure. There are currently no cures for ALS, and few effective treatments for slowing progression of the disease.
About 1 in 10 cases of ALS are inherited conditions, and about 1 in 5 of the inherited cases is traced to a mutation in the superoxide dismutase 1 or SOD1 gene. Some 200 mutations in the SOD1 gene are associated with ALS that change the amino acids in proteins expressed by the gene. In addition, the mutations cause the gene to over-express, where reducing these protein levels could help patients with ALS.
The team led by Washington University neurologist Timothy Miller tested an experimental drug designed to reduce production of SOD1 proteins. The drug, now code-named BIIB067, was developed by the biotechnology company Ionis Pharmaceuticals in Carlsbad, California and licensed to biopharmaceutical company Biogen for clinical trials. Ionis creates antisense drugs, which uses short DNA or RNA sequences, called oligonucleotides, designed to complement a specific gene sequence. Antisense drugs, says Ionis, interact precisely with a specific sequence of RNA, with many of the therapies in its pipeline binding to messenger RNAs, or mRNAs, and blocking the production of disease-causing proteins.
Miller and colleagues tested a newer formulation of the drug designed to more efficiently block SOD1 production in lab mice and rats. The animals were genetically modified to carry a mutated SOD1 gene, and after a few months began to display difficulty in walking and feeding. The mutated mice were randomly assigned to receive 2 doses of antisense oligonucleotides like BIIB067 or a placebo, after 50 and 92 days. Mice given BIIB067 lived 5 weeks or 22 percent longer than those given the placebo. The same pattern occurred in rats, where the animals given the drug lived 8 to 9 weeks longer than placebo recipients.
The lab rodents given the antisense drug also showed more qualitative improvements than those receiving placebos. Mice and rats given the drug were more likely to maintain their weight than placebo recipients. And 9 week-old mice with the mutated gene also improved some muscular functions over the next 8 weeks when given the drug, while mice receiving the placebo continued to decline. Other signs of neuromuscular damage declined in both drug and placebo recipients, although placebo recipients declined faster than those getting the drug.
Biogen and Ionis are testing BIIB067 in an early stage clinical trial among 84 participants with ALS in the U.S., Canada, and Europe. The trial is testing the drug’s safety and tolerability, to find an optimum dosage, but the study team is also measuring SOD1 protein levels in participants’ cerebrospinal fluid.
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