Bristol-led research investigates treatment of mitochondrial diseases using gene editing

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By Nicky Kobayashi-Boyd, Third Year Biology

A new study, conducted by University of Bristol researchers, makes advances in the realm of gene editing.

The development of gene editing techniques in the 2000s marked the beginning of a biological revolution. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is currently the most powerful, yet simple, form of gene editing.

The technology made headlines after a doctor infamously used it to edit the genes of twins born in China- something that sparked legal and ethical concerns.

CRISPR uses a protein (originally extracted from bacteria) which can cut and remove a specific bit of DNA from our cells, inserting new DNA in its place. DNA is the building block of life: an essential molecule which makes up all our genes, dictating our characteristics and behaviour.

The opportunity for affordable and accurate genetic editing, provided by CRISPR technology, has opened a Pandora’s box of future possibilities.

From treating genetic diseases to designer babies, the ethics are a minefield but the prospects are sensational.

The study was conducted by Jon Lane, Mark Szczelkun and their team at the University of Bristol’s School of Biochemistry, with focus on mitochondria – the cell’s power plants. Although all cells in the body contain DNA, the mitochondria contain their own unique set (mtDNA) which can be modified.

DNA from the nucleus has previously been successfully edited using CRISPR technologies, but working with mtDNA has remained difficult since it's less stable. Though mtDNA only makes up 1% of the human body’s genes, mutations to it can cause serious disease.

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) is one of the most common syndromes stemming from mutations in the mitochondria. Despite only being caused by a single molecular change in the mtDNA strand, the resulting syndrome affects the entire body with a host of symptoms.

MELAS is a prime candidate to try and repair with CRISPR treatment, as the individual mutated DNA segment can be cut from the patient and replaced with the correct one.

The Bristol-led study uses CRISPR to target the MELAS mutation and the trials suggested that a MELAS patient could be treated successfully with this gene editing technique.

The study outlines possible solutions to challenges presented by mtDNA editing. The scissor-like protein that cuts the DNA in the CRISPR process can be found in multiple different forms. Previous research on mtDNA CRISPR techniques uses a specific protein known as Cas9. However, though a common protein choice for CRISPR procedure in the past, the researchers found that applying Cas9 to the mitochondrial genes, damages it and would effectively kill the cell.

To solve this issue, Mark; Jon and their team proposed that future mitochondrial gene editing uses another form of this protein called Cas12a instead. This protein was found to be the most successful for treating MELAS-diseased mitochondria.

There is another problem which regularly impedes attempts to use CRISPR on mitochondrial DNA: CRISPR relies on using small strands of genetic material called RNA. This RNA would therefore also need to enter the mitochondria, alongside the CRISPR protein, in order to successfully edit it.

How RNA can be inserted into the mitochondria, in a healthy body, is relatively unknown. The Bristol researchers therefore investigated known RNA strands that are naturally imported into our cell’s mitochondria. These known strands have ‘import signals’ which act as a flag to our cells, telling it to insert the RNA molecule into the mitochondria.

The researchers were able to cut the import signals from these known RNA molecules and attached them to the CRISPR RNA they were using for MELAS treatment. The cell was then tricked into inserting the CRISPR RNA into the mitochondria instead.

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Caution is voiced by the authors, as the fragility of DNA and the harsh consequences of incorrect gene editing mean that CRISPR can only be used for human treatment when researchers have utmost confidence in its accuracy.

The team’s findings help pave the way to mitochondrial gene editing, without damaging the body’s DNA. Which, in turn, suggests a future of effective treatments for those suffering from mitochondrial diseases- which are currently untreatable.

Banner image: Pixabay / Arek Socha


Do you think more caution should be taken when gene-editing?

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