Translating Genetic Discoveries into Rheumatic Therapies

James King-Holmes / Science Source

SAN DIEGO—Will rheumatologists soon be able to use data from genetics and genome-wide association studies to more accurately predict disease and develop new therapies for rheumatic diseases? At a Nov. 5 session at the 2017 ACR/ARHP Annual Meeting, experts shared their views on how to glean this useful knowledge from genomics studies.

The cost to develop drugs is rapidly increasing, and despite long development pipelines with complex regulatory pathways, many drugs still fail in Phase II clinical trials due to lack of efficacy, said Soumya Raychaudhuri, MD, PhD, associate professor of medicine, Harvard Medical School, and professor of medicine, University of Manchester. According to a 2012 study, since 1995, the number of new molecular entities approved by the U.S. Food and Drug Administration has plateaued, with fewer new therapies being approved for every $1 billion spent in development.¹

“We need strategies to come up with better drug targets, and possibly, genetics is one way to get there,” he said. “The implication is that if we pick our targets better in the first place, we may do better in terms of bringing drugs to market.” To improve therapeutic target validation to develop more effective treatments for rheumatic diseases, genetics likely holds the key.

Dr. Raychaudhuri

“Genetics has obviously come to the forefront of drug development strategies, just as the cost of sequencing has rapidly dropped, and also the cost of genotyping has rapidly dropped,” said Dr. Raychaudhuri. “In the last 10 years, our ability to genotype samples very quickly using conventional SNP-based arrays has also allowed us to do incredible genetic studies.” Analysis of SNPs, or single nucleotide polymorphisms, help reveal slight allele frequency differences between cases and controls in study cohorts, and even small differences may be highly statistically significant.

“In 1987, all we knew was the MHC locus but since then, there has been a rapid escalation in the number of loci discovered in RA,” including novel risk loci. More than 100 RA-associated loci are now known. A large genetics and genome-wide association study may reveal SNPs that point to genes in the same pathway that could be useful in RA drug discovery, he said.²

Genetics in Drug Discovery

One gene discovered through genetics and genome-wide association studies that led to lifesaving drug discoveries was PCSK9, said Dr. Raychaudhuri. The original motivation to investigate this gene was its role in familial hypercholesterolemia (FH), a rare inherited condition that lowers the body’s ability to remove LDL cholesterol from the blood. Although FH is rare, researchers set out to learn more about the complex phenotype of cholesterol biology in the hope of helping a wider patient population affected by high cholesterol, he said.