Mitochondrial Disease

What Are Mitochondria?
Mitochondria are the “energy factory” of our body. Several thousand

mitochondria are in nearly every cell in the body. Their job is to process
oxygen and convert substances from the foods we eat into energy. They
are like power stations, supplying the energy our cells need to function.
Mitochondria produce 90% of the energy our body need. Cells make up
tissues and organs in our bodies, for example the heart and liver. If our
cells do not have enough energy, the tissues or organs do not work
properly. In much the same way, if power stations do not produce
enough energy there will be areas of blackout, where parts of the country
cannot function.
What are mitochondrial diseases?
When mitochondria cannot convert food and oxygen into life-sustaining
energy, cell injury and even cell death follow. When this process is
repeated throughout the body, organ systems begin to fail and even stop
functioning. Mitochondrial diseases can be present at birth but can also
occur at any age.
Mitochondrial diseases can affect almost any part of the body, including
the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or
pancreas.
Mitochondrial dysfunction occurs when the mitochondria don't work as
well as they should due to another disease or condition. Many conditions
can lead to secondary mitochondrial dysfunction and affect other
diseases, including:
-Alzheimer’s disease.
-Muscular dystrophy.
-Lou Gehrig’s disease.
-Diabetes.
-Cancer.
The parts of the body commonly affected are those that have the highest
energy demands, such as brain, muscle, liver, heart and kidney. When
these systems are effected Mitochondrial Disease is usually progressive.
Treatments?
Unfortunately, there is no cure for Mitochondrial Disease at present.
Treatment is usually supportive, relieving the symptoms that can
develop, for example, treating seizures with medication. Doctors can
also try to make energy production more efficient, using co-factors and
vitamins. Examples of these are Ubiquinone (Coenzyme Q10), Thiamine
and Riboflavin. Some people find that using a special diet can help and
this varies depending on which part of the energy production process is
affected. However, this should only be tried with guidance from your
metabolic team.
Gene therapy for mitochondrial diseases.
The recent success of gene therapy across multiple clinical trials has
inspired a great deal of hope regarding the treatment of previously
intractable genetic diseases. This optimism has been extended to the
prospect of gene therapy for mitochondrial disorders, which are not only
particularly severe but also difficult to treat. However, this hope must be
tempered by the reality of the mitochondrial organelle, which possesses
specific biological properties that complicate genetic manipulation. In
this perspective, we will discuss some of these complicating factors,
including the unique pathways used to express and import mitochondrial
proteins. We will also present some ways in which these challenges can
be overcome by genetic manipulation strategies tailored specifically for
mitochondrial diseases.
Despite this remarkable progress, gene therapy for inherited
mitochondrial disorders may present a unique and fascinating set of
challenges that are not fully appreciated by those less acquainted with
mitochondrial biology. Mitochondria are, of course, integral to the
functioning of the cell, producing the bulk of the energy (in the form of
ATP) needed by the cell through the process of oxidative
phosphorylation (OXPHOS). The consequences of mutations in the
mitochondrial genome (mtDNA) and mitochondria-related nuclear genes
are often severe, and the prognosis of such a patient is usually quite
poor. Thus, the value in being able to correct such genetic defects in
patients is readily apparent. Gene therapy and CRISPR gene editing
provide a great deal of promise in the field of medical genetics but have
certain limitations in the treatment of mitochondrial diseases that must
be addressed if they are to be employed successfully in this context. In
the present review, we hope to address this issue by discussing ongoing
clinical trials in the use of gene therapy and gene editing technologies to
treat genetic diseases, with a particular focus on specific challenges in
the use of such approaches for treating mitochondrial diseases.
Gene replacement therapy based around the AAV2 vector has shown
modest, but promising, success in mice for a variety of nuclear-encoded
mitochondrial disease genes. However, the only primary mitochondrial
disease currently involved in active clinical trials of gene replacement
therapy is Leber’s hereditary optic neuropathy (LHON), caused by
mutations in the mitochondrially-encoded MT-ND4 gene. Multiple trials
are currently investigating the treatment of LHON using AAV2 vectors
and MT-ND4 coding sequences modified to carry an MTS. In general,
these trials have produced some improvements in visual function for
patients suffering from LHON, particularly in those with a disease
course shorter than 2 years prior to the time of treatment. However, it
has been noted in at least one of the trials (NCT02652780) that injection
of the viral vector into one eye also restored function in the uninjected
eye. A qPCR-based analysis appeared to explain this result by showing
that the viral vector could be detected in tissues extract from both the
injected as well as the uninjected eye. This may suggest that viral vector
was transferred from the injected to the uninjected eye via the optic
nerves at the optic chiasm, although this mechanism has yet to be fully
confirmed. Overall, however, the results of these trials have been
generally encouraging, and there is reason to believe that other
mitochondrial disease genes may be similarly amenable to gene
replacement therapy, so long as protein import and expression level
issues are properly addressed. Thus far, very few clinical trials have
been conducted with nDNA-related mitochondrial diseases.

Mitochondrial Disease

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What Are Mitochondria?

Mitochondria are the “energy factory” of our body. Several thousand

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