Study in mice shows potential for gene-editing to tackle mitochondrial disorders

Date:
February 8, 2022
Source:
University of Cambridge
Summary:
Defective mitochondria -- the 'batteries' that power the cells
of our bodies -- could in future be repaired using gene-editing
techniques.

Scientists have now shown that it is possible to modify the
mitochondrial genome in live mice, paving the way for new treatments
for incurable mitochondrial disorders.



FULL STORY ========================================================================== Defective mitochondria -- the 'batteries' that power the cells
of our bodies - - could in future be repaired using gene-editing
techniques. Scientists at the University of Cambridge have shown that
it is possible to modify the mitochondrial genome in live mice, paving
the way for new treatments for incurable mitochondrial disorders.


==========================================================================
Our cells contain mitochondria, which provide the energy for our cells
to function. Each of these mitochondria is coded for by a tiny amount of mitochondrial DNA. Mitochondrial DNA makes up only 0.1% of the overall
human genome and is passed down exclusively from mother to child.

Faults in our mitochondrial DNA can affect how well the mitochondria
operate, leading to mitochondrial diseases, serious and often fatal
conditions that affect around 1 in 5,000 people. The diseases are
incurable and largely untreatable.

There are typically around 1,000 copies of mitochondrial DNA in each cell,
and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually,
more than 60% of the mitochondria in a cell need to be faulty for the
disease to emerge, and the more defective mitochondria a person has,
the more severe their disease will be. If the percentage of defective
DNA could be reduced, the disease could potentially be treated.

A cell that contains a mixture of healthy and faulty mitochondrial DNA is described as 'heteroplasmic'. If a cell contains no healthy mitochondrial
DNA, it is 'homoplasmic'.

In 2018, a team from the MRC Mitochondrial Biology Unit at the University
of Cambridge applied an experimental gene therapy treatment in mice and
were able to successfully target and eliminate the damaged mitochondria
DNA in heteroplasmic cells, allowing mitochondria with healthy DNA to
take their place.



==========================================================================
"Our earlier approach was very promising and was the first time that
anyone had been able to alter mitochondrial DNA in a live animal,"
explained Dr Michal Minczuk. "But it would only work in cells with enough healthy mitochondrial DNA to copy themselves and replace the faulty
ones that had been removed. It would not work in cells whose entire mitochondria had faulty DNA." In their latest advance, published today
in Nature Communications, Dr Minczuk and colleagues used a biological
tool known as a mitochondrial base editor to edit the mitochondrial DNA
of live mice. The treatment is delivered into the bloodstream of the
mouse using a modified virus, which is then taken up by its cells. The
tool looks for a unique sequence of base pairs -- combinations of the A,
C, G and T molecules that make up DNA. It then changes the DNA base - -
in this case, changing a C to a T. This would, in principle, enable the
tool to correct certain 'spelling mistakes' that cause the mitochondria
to malfunction.

There are currently no suitable mouse models of mitochondrial DNA
diseases, so the researchers used healthy mice to test the mitochondrial
base editors.

However, it shows that it is possible to edit mitochondrial DNA genes
in a live animal.

Pedro Silva-Pinheiro, a postdoctoral researcher in Dr Minczuk's lab and
first author of the study, said: "This is the first time that anyone has
been able to change DNA base pairs in mitochondria in a live animal. It
shows that, in principle, we can go in and correct spelling mistakes
in defective mitochondrial DNA, producing healthy mitochondria that
allow the cells to function properly." An approach pioneered in the UK
known as mitochondrial replacement therapy - - sometimes referred to
as 'three-person IVF' -- allows a mother's defective mitochondria to
be replaced with those from a healthy donor. However, this technique
is complex, and even standard IVF is successful in fewer than one in
three cycles.

Dr Minczuk added: "There's clearly a long way to go before our work could
lead to a treatment for mitochondrial diseases. But it shows that there
is the potential for a future treatment that removes the complexity
of mitochondrial replacement therapy and would allow for defective
mitochondria to be repaired in children and adults." The research was
funded by the Medical Research Council UK, the Champ Foundation and the
Lily Foundation.

========================================================================== Story Source: Materials provided by University_of_Cambridge. The original
text of this story is licensed under a Creative_Commons_License. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Pedro Silva-Pinheiro, Pavel A. Nash, Lindsey Van Haute, Christian D.

Mutti, Keira Turner, Michal Minczuk. In vivo mitochondrial
base editing via adeno-associated viral delivery to mouse
post-mitotic tissue. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-28358-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220208085000.htm
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