Alnylam Pharmaceuticals announced this week that it has added cystic fibrosis to the list of diseases for which it is exploring the use of RNAi-based therapeutics.
The company said that it has formed a collaboration with Cystic Fibrosis Foundation Therapeutics — the drug-discovery and -development affiliate of the Cystic Fibrosis Foundation — to discover siRNAs that restore the proper function to the cystic fibrosis transmembrane conductance regulator, a protein required for the transport of salt and water across the cell membrane. Defects in this protein result in the abnormally thick, sticky mucus associated with CF that clogs the lungs and leads to life-threatening lung infections, according to the CFF.
According to Nagesh Mahanathappa, senior director of business development and strategy at Alnylam, the use of RNAi to target this protein is a novel one.
“The predominant form of CF is one in which the mutant CFTR protein … is captured by the cell’s own ‘quality-control machinery’ — chaperones, ubiquitin-ligases, etc. — and is shunted into the protein-degradation pathway rather than targeted to the cell surface,” he said in an e-mail to RNAi News. “The idea behind an RNAi therapeutic in this case is actually to silence some of these quality control proteins so as to let the mutant CFTR reach the cell surface.
“There is an in vitro precedent for our strategy inasmuch as deleting certain quality-control proteins does allow mutant CFTR to reach the cell surface,” Mahanathappa added.
He said that “over the years it has also been made clear that if the mutant CFTR reaches the cell surface, it can mediate chloride flux, [which] is CFTR’s normal function. Thus, in this program we will be testing siRNAs directed against a number of quality-control proteins and will assess which show the greatest promise for the restoration of CFTR activity.”
Mahanathappa noted in his e-mail that Alnylam expects an RNAi treatment for CF to be administered as an aerosol. He added that the initial phase of the drug program will focus on “on the identification of the best silencing targets that will result in the restoration of CFTR activity in vitro. Then … we anticipate that we will be able to move forward rapidly into in vivo studies with the guidance and expertise of the Cystic Fibrosis Foundation and their team of consultants,” he said.
Under the terms of Alnylam’s deal with CFFT, the company expects to receive $1.5 million in upfront and milestone payments to support its initial efforts. Additional terms were not disclosed.