User:Katjenkins0520/Cystic fibrosis

Gene Modulators [Small molecules]
A number of small molecules that aim at compensating various mutations of the CFTR gene are under development. CFTR Modulator Therapies have been used in place of other types of genetic therapies. Modulator Therapies focus on the expression of a genetic mutation instead of the mutated gene itself. Currently these modulators are split into two classes: potentiators and correctors. Potentiators act on the CFTR ion channels that are embedded in the cell membrane, and these types of drugs help open up the channel to allow transmembrane flow. Correctors are meant to assist in the transportation of nascent proteins, a protein that is formed by ribosomes before it is morphed into a specific shape, to the cell surface to be implemented into the cell membrane.

Most of the drugs that are used in this process will target the transcription stage of genetic expression. One specific approach is to develop drugs that get the ribosome to overcome the stop codon and synthesize a full-length CFTR protein. About 10% of CF results from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutations such as G542X, which consists of the amino acid glycine in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with protein synthesis and error-correction. In some cases, they can cause the cell to overcome a premature stop codon by inserting a random amino acid, thereby allowing expression of a full-length protein. Future research for these modulators is focused on the cellular targets that can be effected by a change in a gene's expression. Otherwise, genetic therapy will be used as a treatment when Modulator Therapies do not work given that 10% of cystic fibrosis patients are not effected by these drugs.

The aminoglycoside gentamicin has been used to treat lung cells from CF patients in the laboratory to induce the cells to grow full-length proteins. Another drug targeting nonsense mutations is ataluren, which is undergoing Phase III clinical trials as of October 2011.

Trikafta, a CFTR modulator approved by the FDA in October of 2019, is one such modulator that counteracts the patient's phenotype. This drug is a combination of previously developed medicines, and in turn is able to treat up to 90% of cystic fibrosis patients. This drug specifically restores the effectiveness of the CFTR protein so that it can work as an ion channel on the cell's surface. One of the intents that was used during development of this drug was to avoid further lung damage and to tackle the associated issues of bacterial lung infections.