Advances in Mitochondrial Medicine

This special issue of Journal of Inborn Errors of Metabolism and Screening provides an overview of the current state-of-the-art in several important areas of mitochondrial clinical medicine, including updates on clinical presentations, seizure management, use of anesthesia, and approaches to mitochondrial disease therapy. Individual reports herein focus on specific therapies that have been in use or in clinical trials for substantial periods, especially l-arginine and the quinone compounds coenzyme Q₁₀, idebenone, and EPI-743. However, there are a number of other potential therapies that are currently being evaluated in clinical trials, ranging from novel antioxidants to gene therapy. Indeed, as our understanding of the molecular basis of disease improves, treatments have been increasingly focused on specific aspects of mitochondrial disease pathogenesis, such as cardiolipin oxidation, nitric oxide production, and mitochondrial biogenesis signaling cascades (Table 1).

Table 1
Mitochondrial Disease Clinical Trials.

Investigational Agent		ClinicalTrials.gov Identifier		Condition(s)		Interventional Target(s)		Trial Design		Outcome
Coenzyme Q10		NCT00432744		Mitochondrial disorders		ROS		RDBPC		Pending
Idebenone		NCT00747487		LHON		ROS		RDBPC		No change in visual acuity, Improved secondary end points
		NCT00887562		MELAS		ROS		RDBPC		Pending
EPI-743		NCT01642056		Neuromuscular disease with redox imbalance		ROS		RDBPC		Pending
		NCT0|370447		Mitochondrial disorders		ROS		Open- label		Pending
		NCT01721733		Leigh syndrome		ROS		RDBPC		↓ rate of hospitalization and serious adverse events
		NCT01728064		Friedreich ataxia		ROS		RDBPC		Pending
KH176		NCT02544217		Mitochondrial disorders		ROS		RDBPC		Pending
L-Arginine		NCT01603446		MELAS		Nitric oxide		Open- label		↑ aerobic capacity and muscle metabolism
L-Argninine/ L-Citrulline		NCT01339494		MELAS		Nitric oxide		Open- label		↑ nitric oxide production, ↓ lactate (L-Citrulline)
Dichloroacetate		NCT02616484		Pyruvate dehydrogenase deficiency		PDC		RDBPC		Pending
MTP-131		NCT02367014		Mitochondrial myopathy		Cardiolipin		RDBPC		Pending
		NCT02693119		LHON		Cardiolipin		RDBPC		Pending
		NCT03098797		Barth syndrome		Cardiolipin		RDBPC		Pending
RTA 408		NCT02255422		Mitochondrial myopathy		Nrf2/NFkB		RDBPC		Pending
		NCT02255435		Friedreich ataxia		Nrf2/NFkB		RDBPC		Pending
RP103		NCT02023866		Mitochondrial disease		Glutathione		Open- label		Pending
Bezafibrate		NCT02398201		Mitochondrial myopathy		Mitochondrial biogenesis		Open- label		Pending
scAAV2- P1ND4		NCT02161380		LHON		ND4 gene therapy		Open- label		↑ visual acuity in 2 of 5 participants
GS010		NCT02652767		LHON		ND4 gene therapy		RDMSC		Pending
Allogenic HSCT		NCT02427178		MNGIE		Thymidine phosphorylase		Open- label		↑ thymidine phosphorylase in survivors (9 of 24 participants)

• Abbreviations: LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MNGIE, mitochondrial neurogastrointestinal encephalopathy; NFkB, nuclear factor-kB; Nrf2, nuclear factor-erythroid 2-related factor 2; PDC, pyruvate dehydrogenase complex; RDBPC, randomized, double-blind, placebo-controlled; RDMSC, randomized, double-masked, sham-controlled; ROS, reactive oxygen species.

Historically, in order to choose a therapeutic regimen for a given patient, practitioners of mitochondrial medicine have often relied upon personal experience or small case series, typically involving the open-label use of a given compound or various compounds used in a combination “mitochondrial cocktail.”¹ Anecdotal reports, common medical practice, or open-label studies are clearly insufficient to establish an evidence-based approach to care.² Despite the proliferation of potential new treatments of mitochondrial disease, results from nonrandomized and nonblinded studies using such compounds at best should be considered preliminary.³ Nevertheless, open-label trials have the potential to provide useful initial clinical and safety data that may be helpful in developing more definitive studies.

Although randomized, controlled clinical trials in genetic mitochondrial disease have been the exception in the past, more recent studies have embraced rigorous trial design, and this trend will undoubtedly benefit patients in the long run (Table 1).^2,4-6 There are clearly challenges to developing rigorous trials for mitochondrial disorders, including the presence of molecular and clinical heterogeneity, relative lack of robust biomarkers, and current widespread, but inconsistent, use of various dietary supplements as a means of treatment. Nevertheless, as highlighted in a workshop convened by the National Institutes of Health Office of Dietary Supplements, well-designed clinical trials represent an important strategy for developing an evidence base for developing treatments of mitochondrial disease.⁷

Furthermore, the infrastructure to support clinical trials is improving as evidenced by efforts to establish mitochondrial disease registries and collaborations between multiple centers of excellence.³ The North American Mitochondrial Disease Consortium (NAMDC),⁸ mitoNET—German Network for Mitochondrial Disorders,⁹ and the Mitochondria Research and Medicine Society¹⁰ serve as examples of networks of specialist physicians and scientists devoted to improving the care of mitochondrial disease patients through high-quality research and multicenter investigations. Such networks have increasingly interacted with mitochondrial disease patient support groups in order to build connections between clinicians, basic scientists, and individuals and families affected by these conditions. Support groups will clearly play an increasingly important role related to clinical trial recruitment not only by serving as an interface between affected individuals and researchers but also by providing education about the importance of rigorous research and controlled studies to patients and families.

In addition to the relative proliferation of clinical trials for mitochondrial disorders, there has been an increase in efforts to standardize diagnostic and management approaches. For example, members of the Mitochondrial Medicine Society have recently published guidelines on the diagnosis and care of mitochondrial patients after having first surveyed specialist centers throughout North America on practice patterns.^11-14 Clinical guidelines have also been established by other expert centers, such as the Wellcome Trust Centre for Mitochondrial Research in Newcastle, United Kingdom,¹⁵ and members of NAMDC are currently revising research diagnostic criteria for mitochondrial disorders. Another project, the Mitochondrial Disease Sequence Data Resource Consortium, has focused on the development of a central Internet portal to facilitate the compilation and analysis of mitochondrial and nuclear genomic sequence data related to patients with mitochondrial disease.¹⁶ In short, multiple international efforts are underway to improve awareness, diagnosis, management, and translational research related to mitochondrial disorders. These efforts, in combination with continuously improving understanding of the basic underlying mechanisms of disease pathogenesis, offer optimism for the eventual development of effective treatments of mitochondrial disease.

References

• ¹
  Enns GM. Treatment of mitochondrial disorders: antioxidants and beyond. J Child Neurol 2014;29(9):1235-1240.
• ²
  Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics 2013;10(2):307-319.
• ³
  Pfeffer G, Horvath R, Klopstock T, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol. 2013;9(8):474-481.
• ⁴
  Stacpoole PW. Why are there no proven therapies for genetic mitochondrial diseases? Mitochondrion 2011;11(5):679-685.
• ⁵
  Stacpoole PW, deGrauw TJ, Feigenbaum AS, et al. Design and implementation of the first randomized controlled trial of coenzyme CoQ(1)(0) in children with primary mitochondrial diseases. Mitochondrion 2012;12(6):623-629.
• ⁶
  Viscomi C. Toward a therapy for mitochondrial disease. Biochem Soc Trans 2016;44(5):1483-1490.
• ⁷
  Camp KM, Krotoski D, Parisi MA, et al. Nutritional interventions in primary mitochondrial disorders: developing an evidence base. Mol Genet Metab 2016;119(3):187-206.
• ⁸
  https://www.rarediseasesnetwork.org/cms/NAMDC Accessed 24 October 2017.
  » https://www.rarediseasesnetwork.org/cms/NAMDC
• ⁹
  http://mitonet.org Accessed 24 October 2017.
  » http://mitonet.org
• ¹⁰
  http://www.mitoresearch.org/index.html Accessed 24 October 2017.
  » http://www.mitoresearch.org/index.html
• ¹¹
  Parikh S, Goldstein A, Koenig MK, et al. Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges. Mitochondrion 2014;14(1):26-33.
• ¹²
  Parikh S, Goldstein A, Koenig MK, et al. Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management. Mitochondrion 2013;13(6):681-687.
• ¹³
  Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med 2015;17(9): 689-701.
• ¹⁴
  Parikh S, Goldstein A, Karaa A, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12).
• ¹⁵
  http://www.newcastle-mitochondria.com/clinical-professionalhome-page/clinical-publications/clinical-guidelines/ Accessed 24 October 2017.
  » http://www.newcastle-mitochondria.com/clinical-professionalhome-page/clinical-publications/clinical-guidelines/
• ¹⁶
  Falk MJ, Shen L, Gonzalez M, et al. Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities. Mol Genet Metab 2015;114(3): 388-396.

Publication Dates

• Publication in this collection
  2018

History

• Received
  24 Oct 2017
• Accepted
  11 Dec 2018