Inspiration – Cerebral Cavernous Malformation

Healthy human endothelial cells.

Human endothelial cells genetically manipulated to model a rare genetic disease, cerebral cavernous malformation (CCM).

The scientific work is inspired by the more than 7,000 rare diseases that have no treatment.

A word diagram from the dissertation of the scientific work supporting this project

The incredible extent and complexity of the human vasculature (BodyWorlds)

Electron micrograph (false colored) of red blood cells inside an artery. The endothelium is the layer of cells immediately contacting the red blood cells to keep them in the vessel and directly responsible for interacting with them in a variety of ways.

The MRI of a patient with cerebral cavernous malformation - the disease primarily studied in this work. Black circles are hemosiderin deposits (think dried old blood) surrounding vascular lesions. This patient has a genetic form of the disease that can be modeled effectively in human cells (see image 2)

Description

There are at least 7,000 known rare diseases. Taken as a whole at least 25 million Americans are affected by a rare disease. The often arduous quest for a proper diagnosis and treatment by highly specialized practitioners is a huge stress for families who feel lost, and costs our healthcare system greatly. Further, the high cost of drug development combined with relatively small markets has strongly reduced commercial interest in these diseases. More than 95% of rare diseases have no approved treatment.



As an engineer and scientist, I was determined to find a way to treat these diseases. One interesting trend is drug repurposing (sometimes referred to as drug rediscovery or drug repositioning), whereby existing drugs are used for additional or alternative indications from those for which they were originally designed or intended. The classic example of drug repurposing is that of sildenafil (Viagra), intended originally to treat angina, but attaining blockbuster status for the treatment of erectile dysfunction. The vast majority of drug re-purposing successes can be attributed to serendipity or to a reasoned approach based on a deep understanding of a specific disease mechanism. While these reasoned approaches often work for well-studied diseases, a comprehensive picture of the molecular mechanisms underlying many rare diseases are lacking. I knew there must be a better way, and set out to devise one, using a specific rare disease as my test-subject.



Cerebral Cavernous Malformation (CCM) is a hereditary hemorrhagic stroke syndrome characterized by vascular malformations in the central nervous system. CCM lesions are leaky and unstable, with chronic and acute bleeding leading to inflammation and stroke respectively. The only treatment for CCM is neurosurgical resection. CCM occurs in two forms: sporadic and familial, which together affect as many as 1 in 200 individuals in the United States. For my dissertation, I developed an unbiased drug discovery platform for identification of an effective therapeutic for CCM. We used this platform to identify two known drugs as potential treatments for CCM. We found that both of these compounds successfully reduce CCM lesions in a mouse model of human CCM disease, and further demonstrate that these compounds illuminate the pathophysiology of the disease. We have now formed a company, Recursion Pharmaceuticals, to attempt to repeat our work of identifying new uses for known drugs for thousands of rare genetic diseases simultaneously.



I was incredibly excited to work with Candice, who has immense talent, and who was as moved by rare disease patients as I have been. Take a look at her amazing creations based off of the science I’ve worked on for the past 6 years.