Scientific breakthroughs in the past 20 years have advanced our understanding of genetics and its role in causing diseases. These breakthroughs also have ushered in a new era in which doctors can prescribe a particular therapy based on an individual's DNA.
More and more people with cystic fibrosis are benefitting from this type of personalized, or precision, medicine because of the advancement of drugs known as modulators. Each of the four U.S. Food and Drug Administration (FDA)-approved modulators are prescribed for people with CF who have specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
Eventually up to 90 percent of people with cystic fibrosis could benefit from these CFTR modulators. But with more than 1,700 disease-causing mutations of the CFTR gene, CF researchers are trying to increase the number of CFTR mutations that these drugs are approved to treat. To do that, they are working on a process called “theratyping.” Essentially, theratyping matches therapies, or medications, to specific types of mutations to allow even more people with CF to reap the benefits of CFTR modulators.
How Will Theratyping Play a Role in Personalized Medicine?
The primary goal of theratyping is to identify which mutations respond to certain CFTR modulators, thereby helping people with rare CFTR mutations gain access to already approved CFTR modulators quickly and safely.
The conventional process for determining whether a drug successfully targets a particular mutation has been through clinical trials in people with CF who have a specific mutation. Clinical trials are feasible when there are enough people with that mutation to test, but this process becomes problematic for individuals whose mutations are so rare that only a handful of other people have them in the world. (About 1,000 of the 1,700 CFTR mutations occur in fewer than five people.)
For this reason, researchers are testing CFTR modulators on cells affected by rare CFTR mutations to see if the proteins they produce show improved function. If the lab tests show positive results, that information is shared with the drug's manufacturer. The pharmaceutical company will use this information to help inform their own research into whether to submit an application to the FDA to expand a drug to new mutations.
The FDA already has demonstrated a willingness to use lab results as a factor in deciding whether to expand eligibility for an approved drug. The agency relied on a combination of lab results, clinical data, and the drug's established safety record to expand the use of ivacaftor to people with CF.
What Are Researchers Doing to Put Theratyping Into Practice?
To understand what needs to be done to implement theratyping, it helps to know more background about how scientists test drugs in the lab.
In preclinical testing -- work done before a drug is tested in clinical trials -- researchers create “models” of a patient's system by taking cell samples from different parts of the body or creating cells expressing mutant versions of CFTR. To conduct numerous tests, they put the cells into a medium where the cells divide into a group of identical cells. This cell line is then used for testing to see how it would potentially act in an actual patient.
Researchers expose the cells to CFTR modulators to replicate what might happen in your body. They look for certain indications as to whether a drug is working.
The Cystic Fibrosis Foundation Therapeutics Lab in Lexington, Mass., houses a collection of cells with different CF-causing mutations, including nonsense mutations which are used to test whether certain compounds may benefit people with nonsense mutations and are worth developing further into drugs.
The lab's scientists also are spearheading a new initiative to collect and grow cells from other people with rare mutations. These cells will be critical for screening potential new drugs and other treatment options for rare mutations, and they will be made available to other CF researchers to advance research. The Foundation is collecting these cells at sites around the U.S. as part of a study called RARE.
In addition to this work, the Foundation supported two observational studies -- GOAL and PROSPECT -- in which researchers tried to match clinical changes in a patient's health after taking a CFTR modulator with changes that can be seen in cells in the lab.
In the PROSPECT study, for example, researchers collected nasal cell samples from individuals with CF to see how these cells responded to lumacaftor/ivacaftor (Orkambi®) in the lab. Then they compared the cellular response to the person's response in real life, to identify new biomarkers in the lab that signal positive or negative health effects. Likewise, in the GOAL study, researchers looked at the effects of ivacaftor (Kalydeco®) on people with CF and compared them to changes observed in the lab. The results of the GOAL and PROSPECT studies are beginning to be analyzed and published with interesting findings in infection, inflammation, and gastrointestinal issues.
In a new study called PROMISE, researchers will be looking at the effect that elexacaftor/tezacaftor/ivacaftor (Trikafta™) has on the overall health of people with CF, including lung function, inflammation, infection, mucus, gastrointestinal symptoms, intestinal pH, glucose regulation, bone health, and liver disease.
The CF Foundation hopes that the findings from these studies will eventually help doctors select the medication that will have the most benefit for individuals. Researchers believe these studies and others like it will lead to a greater understanding of what happens when individuals with CF take CFTR modulators and help provide insights that will lead to treatments for other CF mutations.
In the meantime, the Foundation is working with researchers on the next generation of drugs that will address other mutations as well as therapies that could help all individuals with CF regardless of their mutation.
***
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 the 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.