Restore CFTR: Exploring Treatments for Rare and Nonsense Mutations

The Cystic Fibrosis Foundation is aggressively pursuing potential treatments for people with CF who have nonsense and rare mutations who will not benefit from drugs known as modulators, which correct the malfunctioning cystic fibrosis transmembrane conductance regulator (CFTR) protein.

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Summary
  • For nonsense mutations, 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.
  • Three strategies for restoring CFTR activity in people with nonsense or rare mutations -- which could benefit everyone with CF regardless of their mutations -- are ribonucleic acid (RNA) therapy, gene editing, and gene 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).

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 CFTR modulators that correct the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

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 CFTR protein. Because these individuals do not produce CFTR protein, they cannot benefit from CFTR modulators. They will need different therapies to fix the underlying cause of their disease.

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 (DNA) that is used as a template to create the CFTR protein.

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 protein that the cell recognizes as defective and destroys.

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 screening process to identify compounds in its chemical library that promote readthrough and stabilize mRNA. The CF Foundation, which started the project in 2015, has awarded it up to $9.2 million over five years. The program continues to characterize hits that emerged from its screening process.

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 CFTR gene. The company plans to use the computer modeling process -- a method intended to speed up drug discovery -- to identify and develop “families of molecules” that are suitable to be developed into drugs.

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 screening studies to identify new drugs and other potential treatment options. These cell lines will be made available to companies and CF scientists to advance research in this area. The Foundation has been collecting these cells at sites around the U.S. as part of a study called RARE.

Watch Emily Kramer-Golinkoff, who has two nonsense mutations in her CFTR gene, speak about the importance of the RARE clinical trial with the study sponsor, George M. Solomon, M.D., an assistant professor of medicine and the director of the adult CF program at the University of Alabama-Birmingham.

RNA Therapy

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 molecule and correct these instructions so that a full-length CFTR protein can be made.

Oligonucleotides, including ASOs, provide a potential therapeutic approach for several types of CFTR mutations and are already used in the treatment of spinal muscular atrophy, certain forms of muscular dystrophy, and other genetic diseases.

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.

Gene editing uses the cell's own DNA repair system to correct the mutation in the cell's DNA. Gene therapy is a technique that would supply normal CFTR DNA to cells.

Although gene editing and gene therapy are promising, it will be many years before this type of technology can be applied to cystic fibrosis. Learn more about the most recent research the Foundation is funding on gene editing and gene therapy.

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Reference to any specific product, process, or service does not necessarily constitute or imply its endorsement, recommendation, or favoring by the Cystic Fibrosis Foundation. The appearance of external hyperlinks does not constitute endorsement by the Cystic Fibrosis Foundation of the linked websites, or information, products, or services contained therein.

Information contained on this site does not cover all possible uses, actions, precautions, side effects, or interactions. This site is not intended as a substitute for treatment advice from a medical professional. Consult your doctor before making any changes to your treatment.

FDA-approved drug information is available at dailymed.nlm.nih.gov/dailymed.

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