Advances in Mitochondrial Medicine

Gregory M. Enns Enns About the author

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.

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.”11 Enns GM. Treatment of mitochondrial disorders: antioxidants and beyond. J Child Neurol. 2014;29(9):1235-1240. Anecdotal reports, common medical practice, or open-label studies are clearly insufficient to establish an evidence-based approach to care.22 Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics. 2013;10(2):307-319. 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.33 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. 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).22 Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics. 2013;10(2):307-319.,44 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.
-66 Viscomi C. Toward a therapy for mitochondrial disease. Biochem Soc Trans. 2016;44(5):1483-1490. 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.77 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.

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.33 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. The North American Mitochondrial Disease Consortium (NAMDC),88 https://www.rarediseasesnetwork.org/cms/NAMDC. Accessed 24 October 2017.
https://www.rarediseasesnetwork.org/cms/...
mitoNET—German Network for Mitochondrial Disorders,99 http://mitonet.org. Accessed 24 October 2017.
http://mitonet.org...
and the Mitochondria Research and Medicine Society1010 http://www.mitoresearch.org/index.html. Accessed 24 October 2017.
http://www.mitoresearch.org/index.html...
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.1111 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.
-1414 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). Clinical guidelines have also been established by other expert centers, such as the Wellcome Trust Centre for Mitochondrial Research in Newcastle, United Kingdom,1515 http://www.newcastle-mitochondria.com/clinical-professionalhome-page/clinical-publications/clinical-guidelines/. Accessed 24 October 2017.
http://www.newcastle-mitochondria.com/cl...
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.1616 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. 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
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br