The Shaw Prize in Life Science and Medicine 2022 is awarded in equal shares to Paul A Negulescu and Michael J Welsh for landmark discoveries of the molecular, biochemical, and functional defects underlying cystic fibrosis and the identification and development of medicines that reverse those defects and can treat most people affected by this disorder. Together, these discoveries and medicines are alleviating human suffering and saving lives.
Cystic fibrosis (CF) is one of the most common, severe single-gene disorders, affecting more than 80,000 people globally. The single gene in which the disease-causing mutations fall is called CFTR (cystic fibrosis transmembrane conductance regulator). The CFTR protein ensures the proper flow of chloride, a component of salt, that is present in secreted body fluids such as sweat, saliva and mucus. These fluids keep cells lubricated and are thus vital for the proper function of organs. In CF patients, these secretions become thick and sticky and, rather than acting as lubricants, clog passageways, especially in the lungs. The disease is fatal. There are many different mutations in CFTR that cause the disease, but a mutation called F508del is particularly important, and is present in about 90% of patients.
Lap-Chee Tsui pinpointed chromosome 7 as harbouring the “CF” gene in 1985. Four years later, in a landmark use of positional cloning for human genetic analysis, Lap-Chee Tsui, Francis Collins, and colleagues cloned the CFTR gene and reported that alterations in the protein caused cystic fibrosis. However, the function of the CFTR protein, how mutations affect its function, and whether that knowledge would enable therapeutic development, remained unknown.
Michael Welsh, working at the University of Iowa, broke through all three obstacles. He first discovered, in 1990/1991, that the CFTR protein is a chloride channel and he revealed how its activity can be regulated. He corrected the CF defect in cultured cells by providing a normal CFTR gene, thereby showing that correcting the defect was a feasible therapeutic strategy. The most obvious way of achieving this, i.e., by gene therapy (delivery of a functional gene), has unfortunately been unsuccessful to date. Instead, therapeutic development was enabled by additional extraordinary studies (1992–1993) by Welsh. He demonstrated how different CF disease-causing mutations affect the CFTR protein ― some eliminated its production, some interfered with its trafficking to the cell membrane, and some prevented the opening or function of its chloride-transporting channel. He showed that the severity of the defects of the CFTR proteins in assays he designed in the laboratory correlated with the severity of the CF disease each caused. Welsh categorized the different human CF mutations according to mechanism and laid out a scheme to correct each type of underlying defect. Importantly, Welsh showed that the CFTR protein with the common F508del mutation has multiple defects, the protein does not reach the cell membrane and is also defective for chloride transport. In a seminal contribution, Welsh discovered that trafficking of CFTR-F580del to the membrane was temperature sensitive. That is, at low temperature, the protein made it to the cell membrane, but at body temperature, it became stalled in an internal cellular compartment, and it did not reach its final, normal location, the cell membrane. Very crucially, Welsh demonstrated that if the CFTR-F508del protein did make it to the membrane, it functioned. That landmark discovery meant that if a strategy could be developed to get CFTR-F508del to the cell membrane, it would be beneficial in combating the disease.
Welsh’s discoveries and his mechanistic insight provided the needed groundwork for Shaw Prize laureate Paul Negulescu to make the leap from mechanism to therapy. Efforts to treat CF with gene therapies had been attempted and failed. Negulescu and his team at Vertex Pharmaceuticals took on the challenge of developing small molecule therapeutics. Doing so was an enormously risky strategy because mutations that cause CF disease are loss-of-function, and so expecting a protein to be “fixed” by the action of small molecule is not standard. Moreover, there are many different mutations that cause disease, so it was not obvious a medicine could be made that is capable of treating many CF patients. Negulescu first discovered a CFTR “potentiator” that stimulated CFTR channel function. This medicine, called Kalydeco, was granted breakthrough designation as a monotherapy for CF. The medicine received regulatory approval exclusively based on laboratory data, not on clinical trial data, a first and a watershed moment for the path to modern clinical development of medicines for rare diseases.
Still, there was a significant hurdle. Kalydeco was useful only for the subset of CF patients with certain rare mutations, not for the vast majority of CF patients with the CFTR-F508del mutation. In an even bolder effort, Negulescu then screened for molecules that could correct the trafficking defect of the CFTR-F508del protein. Remarkably, he discovered such a molecule, a “protein-corrector”. He combined the new molecule with Kalydeco, now named Orkambi. He then improved on Orkambi twice more, combining two “protein correctors” with a “potentiator” to make Trikafta, approved in 2019. Trikafta helps patients with the CFTR-F508del mutation and patients with 177 rare CFTR mutations. Currently, 50% of all CF patients take Vertex CF medicines. The FDA described Vertex’s CFTR modulators as “unique” and “groundbreaking”.
The combined contributions of Welsh and Negulescu represent the complete biomedical arc from basic discovery to application to the saving of lives. They are especially worthy of the Shaw Prize in Life Science and Medicine.
29 September 2022 Hong Kong