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An explainer on genetic therapies and cystic fibrosis

Hundreds of researchers around the world are investigating genetic therapies for cystic fibrosis (CF). Genetic therapies offer the potential of being able to treat everyone with CF, including those who for whatever reason are not eligible for CFTR modulators. Earlier this month we announced funding for a Strategic Research Centre (SRC) grant on developing gene editing therapies, a type of genetic therapy. Here we take a closer look at how gene editing and other types of genetic therapy work and how they could benefit people with cystic fibrosis.

DNA, genes and proteins

Before we delve into the complexity of genetic therapies and how they work, here’s a recap of what DNA, genes and proteins are and how they relate to each other to make our bodies work.

Our bodies are made up of trillions of cells. Within each cell is a copy of our DNA; every cell in the body has the same DNA. DNA is an extremely long chemical, containing the instructions that make us who we are.

Our DNA is organised into genes, where each gene is a specific instruction for the cell to make a specific protein. For example, the CFTR gene makes the CFTR protein. The actual production of a protein from a gene is a multi-step process, one of the steps involves a protein-making-template called mRNA.

 
 
 
 
 
 

Although we hear a lot about the role of genes, it is actually proteins that do all of the work within our cells! When there is a mistake in a gene, this often leads to the production of a faulty protein. For example, a faulty CFTR gene leads to the production of a faulty CFTR protein. Sometimes the fault in the CFTR gene means that no CFTR protein is produced at all.

The aim of genetic therapies in CF is to compensate for the faulty CFTR gene and allow a healthy, working copy of the CFTR protein to be produced. If there are healthy copies of the CFTR protein, this means that the lungs would be healthier.

Cystic fibrosis researchers are exploring several different types of genetic therapies, that work to compensate for the faulty CFTR gene in different ways. These include adding healthy, undamaged copies of the CFTR gene into cells (gene therapy); adding in extra protein-making-templates (known as mRNA therapy); repairing sections of the DNA, and correcting the building blocks that CF genes are made from (gene editing).

Gene therapy – new copies of the healthy CFTR gene

Known as gene therapy, the aim of this method of genetic therapy is to add healthy copies of the CFTR gene into the cells that line the lungs. The cells’ protein-making machinery will read the instructions from the healthy copy of the CFTR gene and make a fully-functioning copy of the CFTR protein. The tricky bit is getting enough of the healthy copy of the gene to where it needs to be in the cell in a safe and effective way. You can read more about gene therapy on the research pages of our website.

mRNA therapy – extra protein-making templates

DNA is stored in a protected compartment within cells called the nucleus. In the production process for making proteins, a copy or ‘template’ of the DNA is made in the nucleus by a similar chemical called ‘mRNA’. mRNA is then transported out of the nucleus and used as a template for making the protein.

When a gene is faulty, as in the case of the CFTR gene in cystic fibrosis, the protein-making-template mRNA will also be faulty. mRNA therapies work by adding undamaged protein-making templates for the CFTR protein into the cell. Like gene therapies, a tricky part of developing an mRNA therapy is working out how to add the healthy mRNA into the cell safely and effectively. In a Venture and Innovation Award project co-funded by the Trust and Action Medical Research, Professor Stephen Hart is developing a way of delivering a potential mRNA therapy for cystic fibrosis.

The gene editing toolbox

Gene editing works by correcting the faulty CFTR gene itself, so that it can make a fully-functioning CFTR protein. A biological tool called ‘CRISPR’ is an important part of all gene editing techniques. The best way of using CRISPR to edit the CFTR gene will depend on which CFTR gene mutation needs to be corrected. Researchers in our new gene editing SRC will be investigating the best way of using CRISPR to correct different mistakes in the CFTR gene. It is a fast-moving area of research as new, more sophisticated ways to use CRISPR are being developed all of the time!

Base editing – the newest CFTR gene editing tool in the box!

DNA is made up of four chemical building blocks called ‘bases’. Each gene within our DNA has its own unique sequence of these bases. When a CFTR gene mutation is caused by the bases being in the wrong order, the technique of base editing works by chemically altering an out-of-sequence base, so that a correct template is made. Researchers within our newly-announced Strategic Research Centre on gene editing will be testing out base-editing techniques as a way to correct the CFTR gene in cystic fibrosis.

To help the Trust fund vital research like this and support people with CF during the COVID-19 pandemic, make a donation today.

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