A rare disease solves the mystery of a common drug

Happy Friday! A recent paper published in the Journal of Experimental Medicine reminded me again of rare disease and drug development. In the paper, the authors report the first cases of complete deficiency of an immune-related protein called PD-L1 (programmed death ligand 1). PD-L1 is one of the targets of a major class of anticancer drugs called ‘checkpoint inhibitors’, which bring billions of dollars in revenue for pharma companies every year. The PD-L1 human knockouts recapitulate one of the many autoimmune adverse effects caused by checkpoint inhibitors—type 1 diabetes. I wrote a small post recently on this. Perhaps, it can be a topic for a future post. But reading this paper reminded me of a Twitter thread that I wrote a year ago on a rare recessive muscle disease caused by deficiency of HMG CoA reductase, the target of another popular class of drugs—statins. I have highlighted this paper on my 2023 roundup and have told the story in the 2023 year-end episode of The Genetics Podcast. Still, it deserves to be a standalone post in my Substack. So, I picked it for this week’s From the Twitter archives post.

From the Twitter archives

A major adverse effect of statins is muscle myopathy (known since 1980). Human genetics have recently shed light on this association. Two independent teams have now discovered that recessive mutations in HMGCR cause a severe form of muscular disease in humans.

HMGCR codes for HMG CoA reductase, which converts HMG-CoA to mevalonate, a rate limiting step in the cholesterol synthesis. Statins act by inhibiting HMG-CoA reductase.

Statins were discovered in the 1970s by a Japanese scientist, Akiro Endo. The statins are, according to WSJ, "the first in a class of medicines that today brings $25 billion a year to pharmaceutical companies." Yet, Endo derived no financial benefit from his discovery. Michael S. Brown and Joseph Goldstein, who got Nobel Prize for cholesterol related work, famously said "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo".

Refer to this fascinating WSJ article on Endo's story: "How One Scientist Intrigued by Molds Found First Statin". Endo’s childhood fascination on the discovery of penicillin by Alexander Flemming was a major inspiration behind the statin discovery. Fascinatingly, the fungal mold that led to the development of breakthrough medicine was found on the rice grains that Endo purchased