CRISPR/Cas9 is an experimental approach for treating cystic fibrosis (CF). The therapy features a novel protein-RNA complex that is designed to address the genetic mutations that cause the disease by editing a patient’s genetics, correcting the mutations themselves.

How the CRISPR/Cas9 approach works

DNA (deoxyribonucleic acid) is a double helix molecule that contains four bases (adenine, cytosine, thymine, guanine) and is located in the cell nucleus of all living organisms, including viruses. The sequence in which the four bases are arranged contains all the biological information that makes each of us unique, and is passed from one generation to another. Since DNA cannot move outside the nucleus, all the instructions to create proteins are transcribed or copied into RNA. One of DNA’s particularities is that it can replicate itself during cell division. This is a critical process, since each new cell needs to have the same DNA as the old one. If a mutation occurs at the DNA level, the error is transmitted to RNA and to the protein.

CF is a genetic disease caused by a mutation that occurs in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Normal CFTR proteins serve as channels to allow the transport of water and charged ions (e.g., chloride) in and out of cells, creating a thin mucus that protects and lubricates internal organs (like the lungs and pancreas). The defective CFTR protein leads to an imbalance of water and ion flow in and out of cells, resulting in thick mucus that obstructs airways and traps bacteria. Chronic inflammations and infections are common in people with CF for this reason. CF therapies can target DNA, RNA, or proteins, but only at the DNA level can the mutated CFTR gene be replaced and CFTR function be restored.

Editas Medicine’s approach relies on gene editing, in which the wrong DNA sequence of the defective CFTR gene is replaced by the correct one using the CRISP/Cas-9 technology. CRISPR/Cas9 uses a protein-RNA complex composed of an enzyme (or protein) — Cas9 — bound to a guide RNA (gRNA) molecule that recognizes the wrong DNA sequence and cuts it out. The cell can then fill the excised portion with the correct gene sequence. The delivery mode is expected to be by adeno-associated virus (AAV) or lipid nanoparticle (LNP).

CRISPR/Cas9 research & development

Cystic Fibrosis Foundation Therapeutics — the nonprofit affiliate of the Cystic Fibrosis Foundation — announced a three-year agreement with Editas Medicine in May 2016. The company is being given up to $5 million to develop CRISPR/Cas9-based medicines for the treatment of cystic fibrosis (CF), targeting not only the most common mutations but also those not addressed by current approaches (there are some 1,800 known mutations in the CFTR gene). As part of the agreement, Editas will also gain access to a network of CF specialists.

Editas’ research in this CF treatment is still in the early stages. However, the recent study “Functional Repair of CFTR by CRISPR/Cas9 in intestinal Organoids of Cystic Fibrosis Patients” demonstrated the use of CRISPR/Cas9 technology in a model of intestinal stem cell organoids from CF patients. The defective CFTR gene was replaced and CFTR function restored, demonstrating the potential use of this technology to correct mutated CFTR genes.

Application of CRISPR/Cas9 technology is also being investigated for the treatment of Duchenne muscular dystrophy, hemophilia, and cancer.

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