“This level of silencing, coupled with the lack of adverse effects, suggests that this approach to treating ALS should be safe in humans and also that therapy can potentially be done with a one-time treatment,” Christian Mueller, PhD, the study’s senior author and a professor of pediatrics at University of Massachusetts (UMass) Medical School, said in a press release.
The research, “Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques,” appeared in Science Translational Medicine.
Familial ALS cases account for nearly 10% of total cases. In 1993, a team led by Robert H. Brown Jr., MD, PhD, also a study author, found the first gene associated with familial ALS – SOD1, which encodes a protein that breaks down toxic oxygen molecules called superoxide radicals.
SOD1 activating mutations underlie about 20% of all familial cases. Because altered SOD1 protein has also been identified in cases of sporadic (non-inherited) ALS, suppressing SOD1 gene expression is regarded as a potential strategy to prevent the death of motor neurons, a hallmark of ALS.
Research in mouse models of ALS has suggested that a process called RNA interference (RNAi) using artificial microRNAs (miRNAs) — tiny molecules that prevent some genes from producing the corresponding protein — may have therapeutic effects. In particular, turning off SOD1 production in mouse models of ALS increased survival, delayed disease onset, and preserved muscle strength as well as motor and respiratory functions.
The team from UMass Medical School tested the efficacy and safety of intrathecal (through the spinal canal) delivery of a modified, harmless virus that encoded an SOD1-targeting artificial miRNA in primates. The investigators used a viral subtype shown to be safe in clinical trials.
To target as many of the 185 ALS-linked SOD1 mutations as possible, the scientists identified common features in the DNA sequences of the mutations. “This approach allows us to target the vast majority of the patients with an SOD1 mutation using a single drug,” Mueller said.
The results showed efficient viral delivery and reduction of SOD1 protein levels by as much as 93% in motor neurons, which control muscle contraction. Higher amounts of miRNA correlated with greater SOD1 gene silencing in motor neurons.
Neither miRNA-induced liver toxicity nor immune reactions was found. Also, the miRNA molecule did not affect other genes with similar sequences, a concern with other gene therapy techniques.
“These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1-linked ALS,” the team stated.
“What this shows is that we have a great way of delivering an RNAi-based drug to the right cells, in sufficient quantities that we should be able to silence the disease-causing gene with a one-time treatment,” Mueller said. “These experiments are at a point where they need to be taken to the next step and translated into clinical trials for patients.”
An expanded access clinical trial of this approach is under way.