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Consortium Spotlight: Advancing Discoveries in Mitochondrial Diseases

June 3, 2022

The North American Mitochondrial Disease Consortium (NAMDC) was established to create a network of clinicians and clinical investigators in North America who follow sizeable numbers of patients with mitochondrial diseases and are involved or interested in mitochondrial research. Here, Principal Investigator (PI) Michio Hirano, MD, shares the history of the consortium, current research, and future plans.

What are the overall goals of the NAMDC?

As a member of the Rare Diseases Clinical Research Network (RDCRN), the NAMDC has established a network of 17 clinical centers whose mission is to improve diagnosis and care, establish natural histories, support translational research in, and investigate treatment of mitochondrial diseases.

Mitochondrial diseases are clinically and genetically heterogeneous disorders caused by primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Our consortium, which acts in close collaboration with key patient advocacy groups—United Mitochondrial Disease Foundation (UMDF), MitoAction, and Muscular Dystrophy Association (MDA)—provides an optimal approach to advancing knowledge of these complex diseases.

How did the NAMDC team come together, and how did you become a part of the RDCRN?

With the support of a two-year National Institutes of Health (NIH) American Recovery and Reinvestment Act (ARRA) grant (RC1NS070232, 9/30/09-9/29/11), we established the infrastructure for the viable and vibrant NAMDC. NAMDC includes an administrative core, a patient registry, draft Mitochondrial Disease Diagnostic Criteria, a Bioinformatics and Biostatistics Core, a Biorepository Laboratory, and extensive shared web resources.

Dr. Salvatore DiMauro (Columbia University Irving Medical Center [CUIMC]) was the PI of the ARRA grant. I was his long-time CUIMC collaborator and co-PI, supported by Dr. J.L.P (Seamus) Thompson, director of the Statistical Analysis Center (SAC) at the Columbia University Mailman School of Public Health (MSPH).

The original NAMDC network consisted of 12 centers of clinical mitochondrial disease excellence across the United States and Canada, plus the UMDF. The NAMDC Clinical Registry, established under NAMDC Protocol 7401, enrolled 112 patients (exceeding the target of 100 patients). The Clinical Registry collects key data on patient demographics and diagnosis, genetic testing, disease manifestations, and family history. Data are also collected on a wide variety of diagnostic tests, including CT, MRI, MRS, and PET scans of the brain; nerve conduction studies and electromyography; echocardiograms, ECGs and cardiac MRIs; and detailed blood and urine analyses. The Registry—which provides the critical foundation for NAMDC activities—accepts patients diagnosed with mitochondrial disease, those with suspected mitochondrial disease, and data from deceased patients with mitochondrial disease.

NAMDC Research Clinical Syndrome definitions for mitochondrial diseases have been drafted. This is a critical advance for the field, given the widespread confusion among clinicians, patients, and researchers about what constitutes a mitochondrial disease. NAMDC has also established a mitochondrial disease biorepository at the Mayo Clinic for the collection and storage of DNA, plasma, cell, and tissue samples.

After building the basic infrastructure of NAMDC with the ARRA grant, we have continued to expand this “operating” consortium with support of a U54 RDCRN cooperative agreement (1U54NS078059, 9/30/11-8/31/14). I am now the PI of NAMDC with Dr. Thompson serving as a co-PI. With this U54 support, NAMDC now has 17 sites and has extended its goals to expand the Registry and Biorepository to diagnose, investigate, and treat specific mitochondrial diseases.

Can you tell us more about the rare diseases you study?

Mitochondrial diseases are challenging to biomedical investigators and clinicians because they are among the most heterogeneous human disorders at every level—clinical, biochemical, and genetic. This is due to the multiple functions of mitochondria besides the classic textbook definition of being the “powerhouse of the cell,” i.e., the main generators of ATP, and to their dual genetic control, dependent—as they are—on both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA).

A pragmatic definition of the mitochondrial diseases that has emerged during the past 30 years initially restricted them to defects of the final energetic pathway, the “business end,” of mitochondrial metabolism that is the respiratory chain (RC)/oxidative-phosphorylation system (OxPhos). Although this definition does considerably reduce the number of diseases under consideration, it still allows for extraordinary heterogeneity, in part because of the RC’s intrinsic complexity and in part because the RC is, in fact, the only mitochondrial pathway under the control of both nDNA and mtDNA. Although only 13 of the approximately 90 proteins that compose the RC are encoded by mtDNA, mtDNA mutations are responsible for a disproportionate number of mitochondrial diseases.

Although the small circle of mtDNA has proven to be a veritable Pandora’s box (over 270 point mutations), mutations in nDNA ought to be even more numerous. The predominance of mendelian mitochondrial diseases is predicated not only on the larger number of nDNA- than mtDNA-encoded respiratory chain subunits, but also on the many nuclear factor functions needed for the proper synthesis, assembly, and functioning of the RC, including components of the mitochondrial protein import machinery, enzymes involved in phospholipid synthesis, and enzymes necessary for the replication, integrity, and translation of mtDNA.

To date, mutations in over 300 nuclear genes are known to cause mitochondrial diseases. A logical extension of the bioenergetic definition of mitochondrial diseases is the inclusion of pyruvate dehydrogenase complex (PDC), an enzyme required for the generation of RC substrates. An additional new and exciting pathogenic category is based on the notion that mitochondria are extremely dynamic organelles, and this new category includes disorders due to abnormal mitochondrial motility, fusion, or fission.

In the current U54 funding period, specific mitochondrial diseases under active investigation include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); pyruvate dehydrogenase complex (PDC) deficiency; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome; Alpers syndrome; Pearson syndrome; and thymidine kinase 2 (TK2) deficiency.

What are your current research projects?

The first three current NAMDC research projects address broad needs of the mitochondrial disease community:

  1. Collecting information and biosamples from subjects with definite or suspected mitochondrial diseases (7401: NAMDC Patient Data Registry and Biorepository)
  2. Genetic diagnosis of mitochondrial disease patients (7418: Genomic Testing for Molecularly Undefined NAMDC Registry Cases)
  3. Functional testing to confirm mitochondrial disease (7415: Mitochondrial Functional Assays in Minimally Invasive Tissues)

Two additional NAMDC projects focus on specific mitochondrial diseases:

  1. Conduct advanced genetic and newborn screening studies of pyruvate dehydrogenase complex deficiencies (7413: Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies)
  2. Physical activity levels and intensity using an ActivPal™ accelerometer in adult and pediatric TK2d subjects

In addition, there are ongoing natural history studies of MNGIE (7403), Alpers syndrome (7405), and Pearson syndrome (7408).

Other ongoing or completed NAMDC pilot projects include:

  1. A phase I multiple ascending dose study of L-Citrulline supplementation for treatment of nitric oxide deficiency in MELAS (7416)
  2. Prototype development of an exome variant analysis pipeline and public interface for the community-wide Mitochondrial Disease Sequence Data Resource (MSeqDR)
  3. An investigation of novel therapies for treatment of combined D, L-2-hydroxyglutaric aciduria
  4. Analyses of one-carbon metabolism in human mitochondrial disorders

How has your research impacted patients?

To engage and learn from patients with mitochondrial diseases, NAMDC has conducted six surveys of patients and caregivers on the following topics:

  1. The use of oocyte nuclear transfer in mitochondrial disease (7404)
  2. Motivations and barriers for participation in clinical trials by individuals with mitochondrial diseases (7410)
  3. Nutritional supplement use in mitochondrial disease (7411)
  4. Cardiovascular events in patients with metabolic disease on chronic carnitine supplementation (7412)
  5. Diagnostic odyssey surveys I (7414) and II (7419)

These surveys have resonated in the mitochondrial disease community by affirming interest in oocyte nuclear transfer to prevent transmission of mtDNA disease; identifying important factors that motivate and prevent participation in clinical trials; demonstrating the widespread use and perception of benefits of nutritional supplements; and documenting the diagnostic odyssey of patients who see, on average, more than eight clinicians before receiving a diagnosis of mitochondrial disease.

The NAMDC Registry has provided further insight into the spectrum of mitochondrial disease in North America. The genetic testing of molecularly undefined NAMDC Registry cases has started to identify causative pathogenic variants, thus providing definitive diagnoses.

Expanded access deoxynucleoside therapy of TK2 deficiency, which was initially funded as an NAMDC project, was so successful in generating preliminary evidence of efficacy that the FDA recommended transfer of subjects into a formal industry or academically sponsored clinical protocol. As a result, almost all subjects in the expanded access deoxynucleoside therapy program have been rolled over into an industry-sponsored phase 2 continuation study. The industry sponsor is planning a follow-up phase 3 trial as well as a formal drug registration application to the FDA and EMA. If successful, this therapy could be the first FDA-approved therapy for a mitochondrial disease.

What new research directions or goals are you pursuing?

NAMDC is continuing its ongoing projects. We are expanding the NAMDC Clinical Registry/Longitudinal Study and Biorepository to attain the target goal of at least 2,000 subjects in the Clinical Registry (1,984 enrolled subjects as of 6/1/2022). A consensus of NAMDC clinical syndrome definitions has been achieved with a publication in press. We intend to accelerate recruitment of subjects for genomic testing as well as continue to advance functional testing in minimally invasive tissues to confirm mitochondrial disease. We intend to complete the genetic and newborn screening studies of PDC deficiencies; the phase I study of L-citrulline for MELAS; and the activity meter study of TK2 deficient subjects.

New avenues of research being pursued in pilot studies include:

  1. In vitro studies of amino acids to enhance the activity of enzymes involved in mitochondrial translation defects (7420)
  2. Development of minimally invasive nanosensor technology to quantify mitochondrial function in human muscle
  3. In vitro analyses of CA5A dysfunction on complex V deficiencies
  4. Assessment of PRISM intervention to promote resilience in stress management in mitochondrial disease patients
  5. Development of a novel microscopy method to assess mitochondrial respiratory chain function in living cells of patients with mitochondrial diseases

How has being part of the RDCRN impacted the work of the NAMDC?

All the work conducted by NAMDC was enabled by the U54 grant and participation in the RDCRN. RDCRN-wide Steering Committee and Fellowship meetings have provided critical exposure to the spectrum of rare disease research in the RDCRN that has stimulated NAMDC activities, such as Registry data mining that was pioneered by the Urea Cycle Disorders Consortium (UCDC). Key collaborations have included the joint funding of a post-doctoral fellow trainee shared by NAMDC and the Inherited Neuropathy Consortium (INC).

The RDCRN-wide COVID survey provided valuable insights into the surprisingly low prevalence of COVID-19 infections in the mitochondrial disease and rare disease communities early in the pandemic.

Support from the RDCRN Data Management and Coordinating Center (DMCC) has provided critical protocol reviews for all NAMDC studies, administration of the NAMDC surveys described above, and data management services for the MELAS L-citrulline phase I trial. There have also been constructive collaborative discussions between the DMCC and NAMDC senior personnel on two major RDCRN goals: the development of procedures to enhance clinical trial readiness, and on trial designs that meet the special challenges of rare diseases.

How do you envision that the diseases you study can ultimately be cured?

Because mitochondrial diseases are clinically, biochemically, and genetically heterogeneous, multiple disease-specific therapies will be required to cure or prevent these debilitating and often fatal disorders. NAMDC has provided a critical infrastructure that is setting the stage for those therapies through clinical trial readiness at multiple levels, beginning with identification of patients and aggregation of clinical information in the NAMDC Clinical Registry and biospecimens in the NAMDC Biorepository.

Improved genetic diagnoses with functional confirmation are critical, along with precise clinical syndrome definitions to meaningfully characterize patients. Surveys of patients have provided critical insights into the perspectives and experiences of patients. Natural history studies have been initiated and need to continue and expand to provide information that will be critical for selecting outcome measures and designing clinical trials. Support of pre-clinical therapeutic studies via provision of biospecimen and pilot testing of therapeutic approaches will enhance chances of successful development of curative therapies.

The North American Mitochondrial Disease Consortium (NAMDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NAMDC is funded under grant number U54NS078059 as a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the Office of Dietary Supplements (ODS).

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