Genetic Therapies and Treatments for Nonsense and Rare Mutations

Cystic fibrosis is a genetic disease. It is caused by mutations — or changes — in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene carries the instructions for making the CFTR protein, which helps keep mucus in the lungs and other organs thin and flowing normally.

When mutations in the CFTR gene disrupt these instructions, the body can’t make CFTR protein the way it’s supposed to. As a result, thick, sticky mucus builds up in the lungs and other organs.

Genetic therapies — including RNA therapy, gene therapy, and gene editing — are designed to treat the root cause of CF by targeting these faulty instructions and allowing the body to make normal CFTR protein. Some genetic therapy approaches aim to provide the body with a new, working set of instructions; others are designed to repair the mutation in a person’s DNA. The benefits of a genetic therapy may be temporary or permanent, depending on the specific type of treatment. Currently, all CF genetic therapies in clinical trials are temporary, inhaled treatments that target the lungs.

Who might benefit from genetic therapies?

While genetic therapies could potentially benefit any person with CF, regardless of their mutations, our priority is to develop new therapies for people who currently don’t have a treatment for the underlying cause of their disease. This includes people with nonsense or rare mutations that cannot be addressed with CFTR modulators, as well as those who can’t take modulators due to side effects or don’t see much improvement from them. Some genetic therapies are designed to work regardless of CF mutation, while others are aimed at helping people with specific types of mutations.

How are genetic therapies different from CFTR modulators?

CFTR modulators:

• Help existing CFTR protein work better, but do not fix the underlying gene
• Don’t work if no CFTR protein is made (common with nonsense and some rare mutations)
• Are taken as daily pills
• Affect the whole body

Genetic therapies:

• Aim to fix or replace the underlying CFTR gene
• Could help all people with CF, even if no CFTR protein is made
• May be long-lasting or one-time treatments
• Are currently being studied as inhaled treatments that target the lungs

RNA therapy and gene therapy are treatments that could potentially help any person with CF, including those with nonsense and rare mutations. They work by providing a new, working set of genetic instructions for the body.

To understand RNA therapy and gene therapy, we need to understand the basic flow of genetic information. When making a protein, the body doesn’t use the instructions in the DNA directly. Instead, it makes a temporary copy of the instructions called messenger RNA (mRNA). The body then “reads” the instructions from the mRNA to build a protein. 

RNA therapy would deliver a new, correct copy of CFTR mRNA to cells, allowing them to make healthy CFTR protein. This type of therapy would not affect a person’s DNA, and the effects would not be permanent, meaning the therapy would need to be re-dosed.

Gene therapy — also called gene transfer — involves delivering a new, correct copy of the CFTR gene to cells. The cells can use the new copy of the gene to create normal CFTR mRNA and then functional CFTR protein. Like RNA therapy, gene therapy provides the correct genetic instructions to the body, but it does not fix a person’s underlying CFTR mutations. Gene therapy would need to be re-dosed. 

Currently, RNA therapy and gene therapy are being tested in clinical trials in adults with cystic fibrosis. Explore the Clinical Trial Finder to see genetic therapy clinical trials that are currently enrolling.

Gene editing is a way to make a permanent change to the cell’s DNA, which could be used to fix a person’s CFTR mutations. After editing, a person’s DNA would contain the correct instructions for making CFTR protein. Some gene-editing methods focus on repairing specific mutations, while others are designed to work across many mutations. A major advantage of gene editing is that, unlike RNA therapy and gene therapy — both of which are temporary — gene editing has the potential to provide a permanent fix. People might need only one treatment with a gene editing therapy to achieve a lasting effect on their disease.

Gene editing therapies have been successfully approved to treat other genetic diseases, such as sickle cell disease. However, gene editing for CF is still in the very early stages. Because it permanently changes a person’s DNA, it carries unique risks and challenges. Although the science is promising, it will likely take many years before gene editing can be tested in clinical trials for people with CF. 

Explore the Drug Development Pipeline to see the full range of genetic therapies we are pursuing in CF, including preclinical lab studies of gene editing approaches.

Antisense oligonucleotide (ASO) therapy is being explored for certain rare mutations, such as splicing mutations, that cause errors in mRNA processing. In CF, splicing mutations can cause extra information to be included in the mRNA. This extra information jumbles up the instructions and prevents the body from making normal CFTR protein.

ASOs work by attaching to the faulty mRNA and hiding the information that shouldn’t be there. This allows the body to use the instructions correctly and make a full-length CFTR protein. ASO therapy does not affect a person’s DNA, and the effects would not be permanent, meaning it would need to be regularly re-dosed.

Oligonucleotides, including ASOs, are already used to treat spinal muscular atrophy, certain forms of muscular dystrophy, and other genetic diseases.

An inhaled ASO drug for people with CF who have the splicing mutation 3849+10Kb C-to-T is currently being studied in a clinical trial.

Nonsense mutations (also known as “x” or “stop” mutations) add an early stop signal to the instructions in mRNA. When the body tries to make a protein, it’s as if the instructions get cut off halfway through. As a result, the body can’t make any CFTR protein, which means CFTR modulator therapies won’t work for people with these mutations.

Researchers are working to find treatments that could help the body override these early stop signals and make a full-length protein. These treatments would be known as readthrough therapies because they “read through” the early stop signals.

Nonsense mutations also shorten the time mRNA remains in the cell. When the mRNA contains an early stop signal, the body recognizes that it’s faulty and destroys it quickly. Therefore, researchers are also looking for ways to stabilize mRNA so it lasts longer in the body. The nonprofit 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. 

In addition, more than 75% of the work at the CF Foundation Therapeutics Lab is dedicated to identifying promising treatments for those with rare and nonsense mutations. Recently, researchers at the lab shared new findings from studies done in cells with the W1282X nonsense mutation. They found that ASO therapy helped the cells make more of a shortened, partially functional version of the CFTR protein. When researchers added existing CFTR modulators, this shortened protein worked better. These results suggest that this approach could help people with W1282X or similar mutations respond to modulators. This is early stage research, and future studies will build on this knowledge to determine whether this approach can be developed into a real treatment for people with CF.

Traditionally, to determine whether a drug works for a particular mutation, people with CF who have that mutation must participate in clinical trials. Clinical trials are possible when there are enough people with the mutation to test, but this process becomes problematic for individuals with extremely rare mutations. Through a process called “theratyping,” the Foundation is supporting lab testing to identify the mutations that respond to approved CFTR modulators. 

Still, approximately 10-20% of people with CF in the United States cannot benefit from CFTR modulators because they are either ineligible or they can’t tolerate their side effects. The REACH study is for all people with CF who do not take CFTR modulators, regardless of their reason. The goal of the REACH study is to help advance new therapies for people with CF who are not taking CFTR modulators. 

REACH is an observational study, meaning that there is no drug or treatment being tested. Participants in REACH will share their de-identified health information and specimens — such as bloodwork — for analysis. Researchers will use this information to inform new clinical trials and advance much-needed therapies.

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