El-Hattab AW, Zarante AM, Almannai M, Scaglia F. Therapies
for mitochondrial diseases and current clinical trials. Mol Genet Metab. 2017
Sep 18. pii:S1096-7192(17)30531-0. doi: 10.1016/j.ymgme.2017.09.009.
[Epub ahead of print]
Abstract
Mitochondrial diseases are a clinically and genetically
heterogeneous group of disorders that result from dysfunction of the
mitochondrial oxidative phosphorylation due to molecular defects in genes
encoding mitochondrial proteins. Despite the advances in molecular and
biochemical methodologies leading to better understanding of the etiology and
mechanism of these diseases, there are still no satisfactory therapies
available for mitochondrial disorders. Treatment for mitochondrial diseases
remains largely symptomatic and does not significantly alter the course of the disease.
Based on limited number of clinical trials, several agents aiming at enhancing
mitochondrial function or treating the consequences of mitochondrial
dysfunction have been used. Several agents are currently being evaluated for
mitochondrial diseases. Therapeutic strategies for mitochondrial diseases
include the use of agents enhancing electron transfer chain function (coenzyme
Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as
energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid,
cysteine donors, and EPI-743), amino acids restoring nitric oxide production
(arginine and citrulline), cardiolipin protector (elamipretide), agents
enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide
bypass therapy, liver transplantation, and gene therapy. Although, there is a
lack of curative therapies for mitochondrial disorders at the current time, the
increased number of clinical research evaluating agents that target different
aspects of mitochondrial dysfunction is promising and is expected to generate
more therapeutic options for these diseases in the future.
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From the article:
Highlights
There are still no satisfactory therapies available for
mitochondrial disorders.
Several agents are currently used and being evaluated for
mitochondrial diseases.
Agents enhancing electron transfer chain function or
mitochondrial biogenesis are used in mitochondrial diseases.
Energy buffer, antioxidants, and cardiolipin protector are
also used in mitochondrial diseases.
Role of liver transplantation and gene therapy in treating
mitochondrial diseases are also discussed.
An increased number of clinical research evaluates agents
targeting different aspects of mitochondrial dysfunction…
Subsequently, different agents aiming to enhance
mitochondrial function and treat the consequences of mitochondrial dysfunction
are presented. These treatment include: 1) agents enhancing ETC function
(coenzyme Q10 (CoQ10), idebenone, riboflavin, dichloroacetate, and thiamine),
2) energy buffer (creatine), 3) antioxidants (vitamin C, vitamin E, lipoic
acid, cysteine donors, and EPI-743), 4) amino acids restoring nitric oxide
production (arginine and citrulline), 5) cardiolipin protector (elamipretide),
6) agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA
408), and 7) nucleotide bypass therapy…
It was suggested that CoQ10 supplementation to individuals
with other mitochondrial diseases would improve the efficacy of electron
transfer through ETC. Some case reports and open-label studies suggested that
CoQ10 treatment may have beneficial effects in individuals with mitochondrial
diseases. However, a randomized double-blinded study only showed minor effects
of CoQ10 supplementation on cycle exercise aerobic capacity and post-exercise
lactate and did not show any effect on other clinically relevant variables such
as strength or resting lactate. Therefore, apart from CoQ10 deficiency, this
supplementation has limited benefits on other mitochondrial diseases…
Thiamine supplementation in a family with MELAS syndrome and
thiamine deficiency was reported to improve lactic acidosis and myopathy. The
use of thiamine, along with CoQ10, carnitine, and vitamins C and E, resulted in
a marked clinical recovery in an individual with adult-onset Leigh disease
presenting as severe brainstem encephalopathy of subacute onset…
Some agents used to treat mitochondrial diseases are
antioxidants that alleviate the toxic effect of excessive ROS produced in these
diseases. Vitamin C and vitamin E are occasionally used in individuals with
mitochondrial diseases in combination with other agents. A limited number of
case reports and small studies has noticed modest benefits for these supplements
in some individuals with mitochondrial diseases...
Flow-mediated vasodilation (FMD), which is a function of NO
synthesized by endothelial cells in response to re-perfusion, was found to be
impaired in individuals with mitochondrial myopathy, MELAS, MERRF (myoclonic
epilepsy with ragged red fibers), MIDD (maternally inherited diabetes and
deafness), and CPEO, providing further evidence of NO deficiency in
mitochondrial diseases. NO deficiency in mitochondrial disorders is believed to
be multifactorial in origin due to impaired NO production and postproduction NO
sequestration ...
The therapeutic effect of arginine in stroke-like episodes
in MELAS is proposed to be due to increased NO availability leading to
improving intra-cerebral vasodilation and blood flow. This has been supported
by the demonstration that arginine supplementation to subjects with MELAS
resulted in increased NO production rate and improved FMD. The use of
oral arginine as maintenance therapy and intravenous arginine during the
stroke-like episodes have become commonly used in treating individuals with
MELAS syndrome.
The clinical effects of citrulline administration in
mitochondrial diseases have not been studied, however, stable isotope studies
have demonstrated that, similar to arginine supplementation, citrulline
supplementation can increase NO production in children and adults with MELAS
syndrome. Interestingly, citrulline supplementation induced a greater increase
in the NO synthesis rate than that associated with arginine supplementation,
indicating that citrulline is a more effective NO precursor than arginine. This
can be due to the superiority of citrulline in raising plasma and intracellular
arginine levels, leading to more arginine availability for NO synthesis...
Currently, a randomized crossover study is conducted to
assess the effect of arginine and citrulline supplementation on endothelial
dysfunction in children with mitochondrial diseases. The primary outcome
measure is the changes in reactive hyperemic index, which reflects endothelial
function, after arginine or citrulline supplementation (https://clinicaltrials.gov/ct2/show/NCT02809170)...
Several agents aiming at enhancing mitochondrial function or
treating the consequences of mitochondrial dysfunction have been used. The use
of these agents is based on limited number of studies and can be beneficial
only in some mitochondrial disease. Therefore, treatment of mitochondrial
diseases remains largely symptomatic and does not significantly alter the
course of the disease. Although, there is a lack of therapies for mitochondrial
disorders at the current time, the increased number of clinical research
evaluating agents target different aspects of mitochondrial dysfunction is
promising and is expected to generate more therapeutic options for these
diseases in the future. Agents currently being evaluated for mitochondrial
diseases include antioxidants (RP103 and EPI-743), cardiolipin protector
(elamipretide), and mitochondrial biogenesis enhancers (bezafibrate,
epicatechin, and RTA 408). Gene therapy has shown promising results in treating
LHON.
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