Gene Editing Has the Potential to Change Cystic Fibrosis

Spiked Columnist, Tim Black, discusses advances in genetic editing in his article, Gene Editing: An Expression of Our Humanity.

Tim Black questions how people should all consider the recent negative responses to some of the latest gene-editing successes. The majority of these gene-editing techniques use a gene-editing tool known as CRISPR-Cas9 that functions to provide solutions for mutations inside of embryos that could lead to several chronic health issues or conditions. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats

CRISPR/Cas9

CRISPR/Cas9 is a novel approach to treating CF with experimental techniques. This therapy utilizes a newly discovered protein-RNA complex that was designed to effectively address and correct genetic mutations that lead to the development of CF by editing the genetics of the patient. The expected delivery mode will most likely be by lipid nanoparticle (LNP) or adeno-associated virus (AAV).

Studies detailing the CRISPR system were first introduced in 2013. The studies implied that CRISP could become a very effective tool for genomic engineering. Since its inception, scientists have been researching the possibility of using CRISPR for several health conditions, including cystic fibrosis, cancer, and HIV. It was in a 2013 issue of the Cell Stem Cell journal, that scientists for demonstrated how they could restore the function of CFTR using the CRISPR systems. The researchers demonstrated this by culturing intestinal stem cells that were donated by CF patients. The study went on to demonstrate how the correct gene was expressed and how full function was returned to the protein

It is known that CF is a genetic disease that is caused by a mutation. The mutation occurs in a specific gene that naturally encodes the CF transmembrane conductance regulator (CFTR). In a normal state, CFTR proteins function as channels that transport water and ions in and out of cells inside the body. As this process continues, the body creates a thin mucus that lubricates and protects several organs inside the body, such as the pancreas and lungs. When they are defective, the CFTR proteins may lead to an imbalance in the body of liquids and ions which can lead to a mucus that is too thick and that clogs the airways. This obstruction can trap bacteria and lead to infections.

There are various CF therapies that could target proteins, DNA, or RNA. At the DNA level, the mutated CFTR gene can be corrected and full function can be restored to the CFTR. Using the CRISPR/Cas-9 technology, Editas Medicine can edit the genes by taking the DNA sequence of a defective CFTR gene and replacing it with a functional one. CRISPR/Cas9 works by using a protein-RNA complex that is composed of a protein (or enzyme). The protein is bound by a guide RNA (gRNA) molecule. The gRNA molecule can identify incorrect DNA sequences and cut them out. The cell then works to fill in the removed portion with the proper gene sequence.

Scientists are still trying to agree on the best method of delivery. There are debates on how exactly the editing apparatus should be delivered into the cells of the patients in order for it to be used as a treatment technique. There are currently only two established methods of deliver for CF gene-editing therapies: in vivo (modifying the cells inside of a living patient) or modifying the cells outside of the patient and then delivering the cells directly to the desired tissues.

However, there are several other innovative methods for delivery that are currently being investigated by researchers. As of recently, scientists used plasmids (circular segments of DNA) to deliver the corrected CFTR genes into the lung cells of patients. This method has been found to be stabilizing to the lung function of research participants with CF. The plasmid delivery option is being investigated in numerous different approaches.

In May of 2016, a nonprofit affiliate of the Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Therapeutics, agreed to give Editas Medicine up to $5 million in order to fully develop the CRISPR-Cas9 therapies for the treatment of CF. The goal of the development is to target both common mutations, as well as less common mutations. There are currently 1,800 known CFTR gene mutations. Editas Medicine will also gain access to a valuable network of CF researchers and specialists. The agreement is currently set for three years and is up for review in 2019.

Responses

The critical responses came almost immediately after a team of research scientists in China first started their clinical trials of a specific treatment with the goal of providing relief for people with aggressive lung cancer in 2016.

Later on, in February of 2017, the American National Academy of Sciences (ANAS) also discussed gene-editing with the release of a report that Black referred to as "cautiously enthusiastic." The report covered the possibility of using gene-editing tools and techniques to get rid of some specific single-gene mutations that are known to cause debilitating and sometimes fatal conditions, such cystic fibrosis (CF).

Additional good news for supporters of gene-editing came in August, 2017, from the Oregon Health and Science University. A research group, comprised of US and Korean members, showed evidence that pointed to the successful modification of human embryos in order to eradicate genetic mutations that can lead to hypertrophic cardiomyopathy. In the Oregon study, about 28 percent of the edited embryos still contained the mutation, but Paula Amago, an author of the study, said that the embryo gene correction method has the potential of preventing the transmission of genetic diseases to offspring and future generations. The study still needs to be proven safe.

However, not everyone feels that the possible future of being able to genetically eradicate a long list of diseases and conditions is a great idea. In fact, a lot of individuals and organizations feel very concerned about the concept.

As Professor Christine Watson of Cambridge University asks, if we genetically modify our embryos by effectively changing our DNA, "are we still human?" This thought process rests on the idea that humanity is a fixed essence and that by changing the elements, you will ultimately change the results.

Black disagrees with this rhetoric and states that it misses the dynamic in the nature of humanity. Black states that humanity is not a thing that can be fixed or defined as such. Instead, humanity is characterized by the capacity to adapt and change. Rather than being stuck or confined to a particular state in nature, humans are continuously in the process of adapting and changing in nature.

References

Black, T. (2017, August 22). Gene Editing: An Expression of Our Humanity. [Web]. In Spiked. Retrieved from: http://www.spiked-online.com/newsite/article/gene-editing-an-expression-of-our-humanity/20230#.WaAKKiiGPIV

CFFT Makes First Major Award to Advance Gene Editing Research in CF (2016, May 16). [Web]. In Cystic Fibrosis Foundation. Retrieved from: https://www.cff.org/News/News-Archive/2016/CFFT-Makes-First-Major-Award-to-Advance-Gene-Editing-Research-in-CF/

CRISPR: A Game-Changing Genetic Engineering Technique. (n.d.). [Web]. In Harvard University. Retrieved on 08/25/2017 from: http://sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/

Lancastre, J. (n.d.). CRISPR/Cas9 Approach for Cystic Fibrosis Treatment. [Web]. In Cystic Fibrosis News Today. Retrieved on 08/25/2017 from: https://cysticfibrosisnewstoday.com/crisprcas9-approach-for-cystic-fibrosis/

Schaffer, C. (n.d.). Could CRIPS Repair CFTR in Cystic Fibrosis Patients? [Web]. In News Medical Life Sciences. Retrieved on 08/25/2017 from: https://www.news-medical.net/health/Could-CRISPR-Repair-CFTR-in-Cystic-Fibrosis-Patients.aspx