UMDF aims to facilitate effective treatments to enhance the lives of those living with mitochondrial disease and one day to find cures. Additionally, we strive to educate the general public, government and private sectors, including medical professionals on mitochondrial disease so that our patient families can access the quality care they deserve. There are hundreds of types of mitochondrial disease identified, and more are being discovered daily. With an estimated prevalence of 1:5000, there are tens of thousands of mitochondrial disease patients in the United States alone, and more than a million world-wide. There are no approved therapeutics in the United States for any of these types of mitochondrial disease, which means there is a huge unmet medical need that must be urgently addressed. While genetic testing has brought significant progress in diagnosing mitochondrial disease patients, the majority still lack a specific diagnosis. While five pharmaceutical companies have conducted clinical trials on hundreds of mitochondrial disease patients to-date, the absence of an FDA-approved drug hinders broader interest from drug developers. Only persistent and committed long-term stewardship of clinical research and care will bring meaningful therapeutics for mitochondrial disease patients. As a global leader in research, education, advocacy and support, UMDF is ideally positioned to steward in a patient-centered way the complex biomedical research ecosystem that ultimately must work in harmony to be successful and fulfill the mission of finding treatments and cures for mitochondrial disease patients.

Advance scientific discovery through our competitive research program. For more than 20 years, the United Mitochondrial Disease Foundation has been the largest non-governmental funder of research focused on the development of treatments and cures for mitochondrial disease. In that time, through the hard work and dedication of our patient families and donors, UMDF has invested nearly $12 million in the best scientific research worldwide that demonstrably advanced the knowledge and understanding of mitochondrial biology while also seeding follow-on funding in excess of $100 million. UMDF is the primary funder of key consortiums and infrastructure initiatives. As we continue to invest in those individuals and organizations that play a pivotal role in advancing discovery they count on us to serve as a steward of both philanthropic and administrative support. Mitochondrial Disease Sequence Data Resource Consortium (MSeqDR) MSeqDR was launched at the UMDF Symposium in Washington, D. C. in 2012 as a (North American Mitochondrial Disease Consortium) NAMDC pilot project. It is a global effort to create an international genomic database for the mitochondrial disease community. This database increases the ability of clinicians to diagnose primary mitochondrial disease and provides them with tools to mine valuable information from many mutations in a secure, confidential atmosphere. North American Mitochondrial Disease Consortium (NAMDC) One of the main activities of NAMDC is to collect information on mitochondrial disease patients and their families in a Clinical Patient Registry. This registry enables research which, due to the rarity of the disease, would not be possible without a large database to collect information on patients from many clinics and countries. Participation in the NAMDC Clinical Patient Registry is a vital step in a new wave of cooperative research into mitochondrial diseases and potential treatments. Patients enrolled in the registry have the option of receiving periodic research updates about mitochondrial diseases, including personal notification of upcoming research projects for which they may be eligible. Mitochondrial Disease Community Registry (MDCR) A robust patient registry is the single most important tool that a rare disease community can have in developing treatments and cures. It empowers patients to contribute to the process in the development of potential treatments and cures through the sharing of their medical, genetic and personal information. The aim of the MDCR is to identify and characterize every person affected by mitochondrial disease, no matter where they are located, living or deceased. Caregivers and family members of those affected, whether themselves affected or not, are also encouraged to register and contribute to the community. The broad involvement of the patient community via a registry is critical in the development of treatments and cures.

UMDF has always considered rigorous peer review as the foundation of good scientific investment. All scientific research grants and investments are reviewed by UMDF staff, members of the UMDF Scientific and Medical Advisory Board and select external experts. Scoring and review include, but are not limited to relevance to UMDF mission and goals, scientific novelty, scientific premise and rigor and potential to impact mitochondrial disease. UMDF invests in basic science to contribute to the understanding of mitochondrial science and mechanisms of pathogenesis; translational science including project that contribute new tools for advancing basic research from benchtop to the clinic, especially novel cellular and animal models or their application to deepen insights, biomarkers, diagnostics, or therapeutics for mitochondrial disease; and clinical research including patient-centered projects which explore means of achieving improved diagnoses, the understanding of the natural history of specific mitochondrial diseases or the development of therapeutic approaches for treating mitochondrial disease. We have the staff dedicated to achieving these goals and lead the mitochondrial disease community in funding the best global biomedical research and hosting our international symposium bringing together the best minds in mitochondrial disease research annually to share the lastest findings in developing effective treatments and therapies.

UMDF will measure success through constant communication with its partners and patient community. We anticipate regular check-ins and annual progress reports related to our goal of better diagnoses, effective therapeutics, and optimal patient care to ensure we are on target. We will utilize surveys and our annual symposium (in excess of 500 researchers, clinicians and family member attendees) to gather feedback from key stakeholders, and use data to ensure our goals are being met. Ultimately, evidence-based data collected through the various registries and repositories will demonstrate whether we have improved the quality of life for patients affected with mitochondrial disease. Our approach is based in rigorous, collaborative scientific investigation. UMDF takes great pride in the alliances we have built over twenty years that underpin our global collaborative partnerships. We recognize that engaging the expertise and knowledge of key stakeholders within the mitochondrial disease community will result in measurable success at a more rapid rate, not just for UMDF, but the entire mitochondrial disease community. Existing collaborations will continue with the Mitochondrial Medicine Society (MMS) and other patient advocacy groups.

• First-ever licensed therapy approved for mitochondrial disease (EU, Leber’s Hereditary Optic Neuropathy). Worked closely with industry partner to develop a regulatory strategy for the US • Identified a portfolio of drug candidates in development within academic institutions of high potential therapeutic value that may now be prioritized, then linked to necessary financial and human resources • Facilitated the review within UMDF’s Scientific and Medical Advisory Board of 3 new clinical trials for mitochondrial disease • Organized meetings to plan and participate in a first-ever meeting in October 2015 with the FDA concerning issues related to the approval of treatments for mitochondrial disease (Critical Path Innovation Meeting) • Developed strategy with the FDA to ensure the regulatory agencies are educated about the “patient voice” in mitochondrial disease drug development. A UMDF-led Patient Focused Drug Development meeting took place on March 29, 2019 to be held in Hyattsville, MD • Collaborated in 2015 with Principal Investigator of the North American Mitochondrial Disease Consortium (NAMDC) to successfully renew a ~$1 million/year NIH grant for 5 additional years of support of a 16-site clinical research network for mitochondrial disease • Coordinated in 2015 the first-ever call for proposals by the Department of Defense (DoD) for the topic of “mitochondrial disease”, opening a new ~$300 million funding opportunity to researchers o Annual participation in promoting and coordinating the DoD call for proposals has resulted in the funding of mitochondrial disease-focused proposals in excess of $20 million between 2015-2018 • Served as central steward together with the NIH in the publishing of a first set of Common Data Elements (CDEs) for mitochondrial disease. These CDEs now serve as the important reference material for researchers around the world when creating new research studies • Fully managed UMDF’s Research Grant Program, providing ~$1,600,000 in seed funds to more than 14 of the most promising scientific projects spanning basic science to clinical research • Developed UMDF’s Roadmap to a Cure in 2016, focusing on increased awareness and improved diagnosis, facilitating therapeutic development and optimized patient care o Launched Roadmap Project in 2018 focused on Leigh Syndrome- a multi-million dollar collaboration with international patient group partners to advance research in a highly collaborative manner over multiple years • Developed and launched the Mitochondrial Disease Community registry (MDCR) on PEER platform in 2014- a patient-populated registry meant to complement the clinician-populated registry already established as part of NAMDC. To date more than 2,400 participants have been recruited, comprised of patients, caregivers and family members • Development and launch of the Mitochondrial Care Network (MCN) in 2018 to optimize the clinical care provided and patient experience in receiving healthcare