Genetic therapies glossary

A type of genetic therapy that might be useful as a treatment for people with CF who have specific CF gene mutations known as ‘splice variants’.

Splicing means removing or cutting out unnecessary parts of a genetic (RNA) sequence in order to form the correct RNA template to make a protein. For some people with CF their CF gene mutations mean that slicing doesn’t happen correctly, and no CF protein gets made. ASO medicines help a correct protein-making template to be made.

Different ASO medicines will need to be designed for each type of ‘splicing’ CF mutation.

See also splicing and splice variants.

A type of treatment which is based on genes, cells or tissues. This includes genetic therapy treatments, cell therapies and tissue engineering / replacement therapies.

This is the gene or DNA sequence that contains the instructions to make the ‘CFTR’ protein. It is sometimes called the CF gene.

People with CF have two faulty copies of this gene, one from their mother and one from their father. Find more information on how CF is inherited.

See CFTR gene. 

The combination of the two types of CFTR gene mutations a person with CF has is known as their ‘CF genotype’. Some genotypes are very common, for example around 50% of people with CF in the UK have two copies of the mutation ‘F508del’. They would some times be referred to as F508del homozygous. Other mutations are extremely rare, where fewer than five people in the UK have the same CF genotype.

Your CF genotype will affect what type of CF medicines will benefit the underlying cause of your CF. People with rare CF genotypes may be unable to benefit from CFTR modulator medicines such as Kaftrio or Ivacaftor, or for others their CF mutations are so rare that CFTR modulators haven’t been tested on them yet.

The numbers of people with different CFTR mutations vary in different countries, and in people with different ethnicities. More information on the CF genotypes in the UK is available in UK CF Registry Annual Data Report.

See Variants

This is a mistake in the CFTR gene, or CF gene, which alters the instructions for making the CFTR protein and causes it not to function correctly (or at all). People with CF have two mutated copies of the CFTR gene.

See the ‘variants’ definition for more information on the different types of CFTR mutation.

See Variants.

CRISPR-Cas9 is used in gene editing research to find and cut DNA in a very specific place. It is adapted from a bacterial self-defence system known as CRISPR. The ‘Cas9’ are the ‘scissors’ that make the cut in the DNA, and a small piece of RNA, known as a ‘guide RNA’ delivers the scissors to the right place in the DNA.

See Vector.

DNA, or deoxyribonucleic acid, is the molecule in our cells that stores a person’s genetic information. Cells in the body contain DNA and use it as instructions to make proteins which allows the body to perform many different functions.

A specific piece, or sequence, of DNA that contains instructions on how to make a particular protein. For example, the CFTR gene that is damaged in CF contains instructions for how to make the CFTR protein.

The aim of gene editing is to repair the existing, faulty CFTR gene itself, so it can make a fully-functioning CFTR protein.

Gene editing works by making a cut in the DNA at a specific place, making a repair, and then sealing up the DNA cut again afterwards. The technique of gene editing became a much more realistic prospect for treating rare diseases with the development of a technique called CRISPR-Cas9.

More recently other types of gene editing are being developed including ‘base’ and ‘prime’ editing.

A type of genetic therapy where a new piece of DNA containing a specific gene is delivered to cells (eg a correct copy of the CFTR gene). Cells can use the correct, newly-delivered copy of the CF gene to create a fully working protein. (The original, faulty copy of the CF gene is still present in cells).

There are two different types of gene therapy (outlined below). In both types, the new piece of DNA does not replace or overwrite any of the person’s existing DNA.

• Integrating gene therapy – the piece of DNA given as treatment is inserted into the person’s genome, becoming a permanent fixture.
• Non-integrating gene therapy – the piece of DNA given as treatment is delivered into the target cells but remains separate from the person’s genomic DNA and is temporary. This means that the treatment would need to be given repeatedly.

Genetic therapy is an umbrella term to include all medicines which involve the use of genetic material (eg DNA, RNA) to treat disease.

Types of genetic therapy include gene therapy, RNA therapy, antisense oligonucleotides (ASOs) and gene editing.

A spherical biological ‘container’ which can be used as a vector to deliver genetic therapy treatments to human cells. Liposomes are made up of a type of fat molecule, or lipid, and can be used to carry genetic therapy treatments.

A type of ribonucleic acid (RNA) molecule which helps translate genetic information from DNA into proteins. Messenger RNA passes on a DNA ‘message’ and acts as a template, carrying instructions for the cell to make a specific protein.

A specific change in a piece of genetic material or DNA sequence, also known as a ‘variant’. Depending on what the change is, and where it occurs, this can determine the effect it has.

Some mutations can have large effects whereas others can have no effect. For example, different mutations within the CFTR gene can affect how the CFTR protein is made or functions (if at all). Mutations or variants can be categorised into specific types, depending on the effect they have on CFTR function. There are 5 broad classes of CF mutation which you can read about here. See the variants definition for more information on specific types of variants.

A mixture of small molecules which can act as a vector for delivering genetic therapy treatment to target cells. Most commonly these are lipid-based nanoparticles which are similar to liposomes.

See Variants.

RNA, or ribonucleic acid is a molecule similar to DNA which contains genetic sequence information.

There are several different types of RNA molecule, including messenger RNA (mRNA). mRNA acts as an intermediate molecule to help 'translate' genetic information from DNA into proteins. In CF, mutations in the CFTR gene will also show up in the mRNA made from the DNA sequence, and this mRNA is used by the cell as instructions to make the CFTR protein.

RNA or mRNA therapy is a type of genetic therapy treatment which would work at the RNA level rather than the DNA level (eg gene therapy works at the DNA level).

RNA therapy treatments could replace the faulty copies of the CFTR messenger RNA with correct versions. This would then allow the cell to read the correct instructions to make fully functional CFTR protein.

RNA therapies need to reach a different part of the cell than gene therapies, so they may be easier medicines to deliver. (RNA therapies work in an area of the cell called the cytoplasm, the main working area of a cell. Gene therapies need to reach a compartment within the cytoplasm called the nucleus).

See Variants. 

The act of removing or cutting out unnecessary parts of a genetic (RNA) sequence in order to form the correct template to make a protein.

In humans, our genes are interspersed with extra bits of sequence (known as introns) which are not needed in the final templates used to make proteins. Splicing is a normal process where the specially marked bits of unnecessary sequence are cut out after the cell copies the gene sequence into an instruction template to make a protein.

In CF, certain mutations called splice variants cause an error with how the bits of unnecessary sequence are removed. This means that some parts remain in the protein-making template or important parts of the instructions are cut out, causing a faulty CFTR protein to be made or no protein at all.

Another name for a specific CF mutation. Researchers studying CF have been able to group together some CFTR variants based on how they affect the production of the CF protein. Some CF genetic therapies will only benefit people with specific types of CF variants. Sometimes the types of CF variant are known as ‘Classes’ of variants.

• Class 1 variants – These are types of CFTR mutation which are also known as ‘stop’ or ‘nonsense’ mutations. They tell the cell to stop production of the CFTR protein too early, so the full, complete protein isn’t able to be made. Treatment types known as ‘readthrough agents’ would work to bypass the ‘stop’ signal in the gene, so that the full protein can be made. Names of Class 1 variants often have an ‘X’ at the end which refers to the ‘stop’ signal.

• Nonsense variants – These are a specific group of Class 1 variants and cause the gene to have an early ‘stop’ signal in the sequence, which results in a shortened CFTR protein.

• Splice variants –types of CFTR mutation which cause errors to be made in creating the protein-making template from DNA. The errors in the template occur due to splicing or cutting errors. Splice variants prevent the cell from making a correct version of the CF protein.

• Missense variants – types of CFTR mutation that causes a change in one of the ‘amino acid’ building blocks that make up the CFTR protein. The effect of missense CFTR variants are different, depending on which building block of the protein is affected. Some variants may have little or no effect on the CFTR protein, while others may cause less protein to reach the cell surface, or affect how well it works.

• Insertion / Deletion variants – Also referred to as ‘indel’ mutations, these are types of CFTR mutation where extra building blocks in the DNA sequence are added (inserted) or removed (deleted) the CF gene. This can cause a dramatic effect on the final CFTR protein that is made and how it functions (if at all).

A vehicle or ‘container’, which holds the genetic therapy and allows the genetic therapy to be delivered into cells. Commonly used vectors are viruses which have been altered so that they don’t cause disease in humans and can’t replicate in the body like normal viruses do. Instead of the virus genetic material, the viral vector will contain the desired genetic therapy treatment. Non-viral vectors such as liposomes or nanoparticles can also be used to deliver genetic therapies.