About 10 percent of people with cystic fibrosis in the U.S. have two rare mutations (including nonsense and missense mutations, splicing defects, frameshifts, insertions, and deletions). Of those, it is anticipated that about 3 percent of these individuals have mutations that may respond to
Through a process called “theratyping,” the Foundation is supporting lab testing to identify the mutations that respond to currently approved CFTR modulators. If any of the tests show positive results, the Foundation will share this with the drug's manufacturer.
Around 7 percent of people with CF have a combination of two nonsense and rare mutations that do not produce
The Cystic Fibrosis Foundation is funding many scientific approaches to develop new treatments for this population through Path to a Cure, an ambitious research agenda to accelerate treatments and drug development for the underlying cause of the disease and ultimately to deliver a cure. These approaches include developing treatments that override premature stop mutations, as well as therapies that repair or replace the CFTR-encoded messenger ribonucleic acid (mRNA) or deoxyribonucleic acid (
Potential Therapies for Nonsense Mutations
Nonsense mutations (also known as “x” or “stop” mutations) cause the production of the CFTR protein to stop prematurely. This leads to a shortened, non-functional
Work is being done to screen for compounds that could enable the protein-making machinery of the cell to override premature stop signals so that a full-length protein can be made. These compounds would be known as readthrough agents because they could “read through” the premature stop signals.
Watch this animation to see how nonsense mutations might be corrected to make normal CFTR protein.
In January 2021, the Foundation awarded up to $2 million to Eloxx Pharmaceuticals to support the global Phase 2 clinical program of ELX-02, a potential readthrough agent to treat people with CF who have nonsense mutations. In May 2021, the Foundation awarded Eloxx an additional $2.6M to screen its library of compounds to identify other potential readthrough agents.
Nonsense mutations also shorten the amount of time the mRNA that codes for the CFTR protein lasts in the cell, thereby decreasing the amount of protein that can be made. Therefore, we are also investigating ways to selectively stabilize mRNA so that it does not degrade as fast.
The nonprofit research organization Southern Research, in collaboration with the University of Alabama at Birmingham and the CF Foundation, has used a sophisticated
In May 2018, the Foundation awarded Icagen Inc. up to $11 million for a multi-year drug discovery program to identify compounds in its chemical library as potential readthrough agents. Icagen also will use computer modeling to simulate how millions of drug candidates might work to suppress the nonsense mutations in the
In addition, the CF Foundation Therapeutics Lab has developed its own screening process and collection of cells with different CF-causing mutations to identify compounds that might be worth developing into drugs. So far, the lab has screened nearly 200,000 compounds to identify those that may work on CFTR nonsense mutations and warrant further development.
The lab's scientists are also spearheading an initiative to collect and grow cells from people with CF with nonsense mutations to increase the diversity of the lab's cell collection. These cells will be critical for
Watch Emily Kramer-Golinkoff, who has two nonsense mutations in her CFTR gene, speak about the importance of the RARE
Ribonucleic acid (RNA) therapy is another potential treatment for those with nonsense and rare mutations that could also benefit everyone with CF regardless of their mutation.
The Foundation is pursuing two different RNA therapy approaches. The first approach is to deliver normal CFTR mRNA to the cells that need to make the CFTR protein.
Watch this video to see how this approach might work.
The second approach involves transfer RNA (tRNA), a key component in the cell's ability to translate DNA into a protein. A company supported by the Foundation is exploring the delivery of a suppressor tRNA that would allow the cell to read through premature stop signals to make full-length CFTR proteins.
Antisense Oligonucleotide Therapy
Antisense oligonucleotide (ASO) therapy is being explored to correct the effects of rare mutations, such as splicing mutations, which disrupt the production of messenger RNA (mRNA). Because mRNA is necessary to make CFTR proteins, splicing mutations block the synthesis of normal CFTR proteins.
A splicing mutation occurs when there is an alteration in the DNA sequence that changes the instructions needed to properly generate mRNA. ASOs are small pieces of DNA or RNA that bind to the RNA
Oligonucleotides, including ASOs, provide a potential
Gene Therapy and Gene Editing
Two strategies for restoring CFTR activity in people with nonsense or rare mutations -- which could benefit everyone with CF regardless of their mutations -- are gene editing and gene therapy. These strategies involve repair or replacement of the DNA.
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