Scientists have learned more about the effects of an experimental amyotrophic lateral sclerosis (ALS) drug candidate that failed its promise. This study has shown that the drug was able to enter the central nervous system (CNS) to reach its intended target, and yet did not improve ALS symotoms. The findings have been reported in Cell.
ALS is a neurodegenerative disorder in which neurons in the spinal cord that control movement gradually die off; this causes a loss of function that becomes more severe over time. ALS can be fatal within five years of diagnosis, but some patients live for much longer.
The disorder can arise from a genetic mutation in which a bit of DNA sequence is repeated too many times within a gene called C9orf72.
An ALS drug candidate, known as BIIB078, is an antisense oligonucleotide (ASO), a short sequence of genetic material that can bind to a complementary sequence and block its effect. BIIB078 aimed to bind to the aberrant part of C9orf72 in ALS patients, and cause it to be eliminated by the cell. This strategy showed positive results in a mouse model, so researchers proceeded to a clinical trial in ALS patients whose disease was traced to mutations in C9orf72.
But the trial was halted, because there was no improvement in the participants’ disease symptoms.
"Disease-specific biomarkers in the cerebrospinal fluid (CSF) suggested that the ASO was hitting its intended target, but it was not clear if it penetrated CNS tissue and affected the disease itself," noted co-corresponding study author Zachary McEachin, Ph.D., an assistant professor at Emory University.
This work revealed that the drug made it into the CNS, and was able to reduce the levels of some disease-related proteins. But it did not help the patients or reduce the accumulation of toxic proteins in the brain.
"Getting the drug to the CNS is only part of the challenge. We need better ways to know whether a treatment is truly changing the course of ALS. Our study addresses some of those questions and shows that CSF biomarkers do not always reflect changes in the CNS,” McEachin added.
The study also revealed variability in how different patients responded to the therapy, showing that we have more to learn about how the range of impacts this method could have.
"Several ASO therapies are either now in clinical use or in trial. We expect our new data will be influential in the development of new ASO-directed therapies," noted co-senior author Professor Jonathan Glass, MD, director of the Emory ALS Center, among other appointments.
The researchers also noted that new biomarkers of ALS are needed so that the efficacy of experimental drugs can be monitored in better ways.
Sources: Emory University, Cell