Tech & Innovation in Healthcare

For researchers, safety is a concern. Find out why.

If a video game has a bug in the software, developers re-write the code and apply a patch to fix the issue. Scientists are applying a similar process to the fight against cystic fibrosis.

Read on to learn how corrected DNA may be the key to cure cystic fibrosis.

Gene Therapy Is a Tool for Tackling CF

Providers are using gene therapy to place a correct version of the cystic fibrosis transmembrane conductance regulator (CFTR) gene inside the patient’s body, so it can provide the blueprint for cells to make normal CFTR proteins. The mutated genes will still be in the patient’s body, but the corrected version is what the body’s cells will look to when producing the proteins.

“It’s a great time to be optimistic. This is a new technology that’s showing promise, not just for cystic fibrosis, but all other genetic diseases and CF is going to lead the charge once again,” says Mitchell Drumm, PhD, Vice Chair of Translational Research, Director of The Research Institute for Children’s Health, Connie and Jim Brown Professor in Cystic Fibrosis Research, and Professor in the Department of Genetics and Genome Sciences at Case Western Reserve University in Cleveland, Ohio.

The Cystic Fibrosis Foundation lists three different versions of gene therapy currently tested by researchers:

• Integrating gene therapy: This method involves using a piece of DNA that holds the correct version of the CFTR gene. Providers deliver the DNA into the patient’s cells, where the new CFTR gene becomes a permanent fixture of the person’s genome.
• Non-integrating gene therapy: Similar to integrating gene therapy, non-integrating gene therapy contains a piece of DNA with the correct CFTR gene. Conversely, the new DNA stays separated from the patient’s genome. The patient’s cells can utilize the correct version of the CFTR gene to produce normal CFTR proteins, but the gene doesn’t disturb the rest of the genome.
• RNA therapy: Ribonucleic acid (RNA) is essentially a working copy of your body’s DNA that cells use to build proteins. With RNA therapy, scientists give the patient’s cells the RNA with the correct CFTR gene directly. These corrected working copies help the body produce normal CFTR proteins. Plus, the RNA doesn’t disrupt the patient’s genome.

No concrete solution: Professor Drumm indicates many types of mutations don’t make any protein, so there isn’t a single answer as to what therapy would work best. “In many cases, it is a single A, T, C, or G that is changed and may be amenable to the various gene editing strategies, but in others it may involve thousands of base pairs of the gene and the technologies to circumvent or repair those will be quite different,” Drumm says.

Find Out How Gene Therapy Administration Works

Since the lung is one of the organs severely affected by cystic fibrosis, researchers are focusing their efforts on the task of delivering gene therapy to lung cells. This is proving to be an immense challenge due to the lungs’ natural defenses, which are mucus and the cell membrane.

A layer of mucus coats the airway and forms a protective layer over the lung cells, and patients suffering from CF have a much thicker mucus layer, which makes the lung cells harder to access. A membrane surrounds each cell in the body to protect the internal contents and block out external threats. If the gene-corrected DNA can get through the thick mucus layer, it will still need to enter through the cell’s protective membrane. For DNA to move through the cell membrane, the genes will require a special coating.

Two methods researchers are testing to introduce correct DNA into cells are chemical coatings and viruses. DNA packaged inside a lipid coating forms a liposome, which can then fuse with the cell’s membrane to allow the DNA to transfer into the cell. Scientists also are testing whether viruses are a viable option. This method involves packaging DNA inside a protein coating to allow the DNA to enter the patient’s cells. However, the viral components can cause inflammation, which could cause the patient to suffer more instead of providing relief.

Oglionucleotide option: Scientists and researchers at the UNC School of Medicine collaborated to develop a new strategy for delivering gene therapy to spliced cells. The researchers connected splice switching oligonucleotides (SSOs) to peptides, so the SSOs can enter the body and into cells. Next, small molecules called OECs allow the oligonucleotides to break out within endosomes. The scientists’ performed their research in a mouse model of a splicing defect that affected a reporter gene, and they observed a positive correction of the defect for at least three weeks following one treatment (URL: academic.oup.com/nar/article/49/11/6100/6295539).

Calculate the Risk of Complications

Fixing the CFTR gene in a patient isn’t like putting a bandage on a cut — it involves re-writing the code of the human body. One of the biggest hurdles to implementing gene therapy in CF patients is “optimizing the editing process and making sure we do no damage,” Drumm says. Researchers have the ability to repair several mutations with different strategies with cells grown in a dish, but to fix enough cells in an entire person? The efficiencies just aren’t there yet.

Safety is another component researchers are coming to terms with. “There is always the possibility for what we call “off-target” effects, where we end up damaging a person’s DNA at an unintended site and causing problems, such as cancer. This looks to be less and less of an issue as the technologies progress and evolve, but it is always something we need to keep in mind,” Drumm says.