Luka Clarke, researcher of the Cystic Fibrosis Research Group at Ciências ULisboa, was awarded 38.5 thousand USD by Emily’s Entourage to investigate a novel strategy for correcting a rare cystic fibrosis causing gene variant.

CF-Splice – Novel splice-switching antisense oligonucleotides (ASOs) for one of the most common CFTR variants in people of African heritage is the name of the research project proposed by Luka Clarke, which has been funded with 38,5 k USD by Emiliy Entourage, an nonprofit organization that raises funds and apply them to accelerate research for new treatments and a cure for individuals with Cystic Fibrosis (CF) that do not benefit from currently available therapies.

Cystic fibrosis is a genetic disease caused by mutations in the gene that produces the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In people with CF, mutations in the CFTR gene can disrupt the normal production or functioning of the CFTR protein. Currently there are several types of CFTR modulators available that can be applied as therapeutic strategy when dealing with certain gene variant types. However, this disease is also caused by rare gene variants like, for example, splice mutations.

To understand how these mutations lead to the production of non-functional CFTR protein, imagine that the instructions to produce it – which are spelled out in a gene – are interrupted by stretches of DNA “letters” that do not code for a protein, the same way an article in a magazine can interrupted by ads. These ads’ beginning and end are marked by a signal. In splice mutations, that signal – that informs the cells where the non-coding portions of DNA start and/or finish – is changed.  Therefore, when the cell tries to read the RNA copy (containing the same instructions as the DNA but in an equivalent alphabet, so to say) it can not recognize where the “ads” begin or end and  it will leave in some irrelevant information or remove important one, being unable to build a correct CFTR protein.

Luka Clarke explains what is the main goal of the project and its impact: “Our proposal is to  characterize and validate the design and delivery of novel splice-switching antisense oligonucleotides (ASOs) for the CFTR variant c.2988+1G>A, which, although rare, is more common in some populations with African heritage, and is not addressed by currently available CFTR modulators.” In fact, if the project reaches its main goal, it will be possible to expand the arsenal of drugs available to fight CF and will be of paramount importance since it will allow ” (…) [to] continue a promising line of previous research (…) [as] ASOs have been approved as drugs for some genetic conditions, but still not for CF”, says the researcher.

This project will also allow Luka Clarke and his team to open new “doors” within the scientific field: “Unlike other drugs, ASOs act at the messenger RNA processing stage, blocking certain steps such as aberrant exon splicing which might be causing the disease. There are various different ways of using them which depend upon the region of the RNA which is targeted. The specific variant we are working with here is a very difficult one to correct, but if we achieve our aims it will represent a real leap forward in the use of splice switching ASOs”, concludes the investigator.

Learn more about this issue on Emily’s Entourage press release.

Find out more about Luka Clarke’s research here.

Discover the work develop by Emily’s Entourage on its website.

Luka Clarke [photo provided by the researcher]