The Leigh Syndrome International Consortium, a patient-driven research network steered by five of the world’s leading mitochondrial disease patient advocacy groups, including Mito Foundation, Mitocon Onlus, People Against Leigh Syndrome (PALS), The Lily Foundation and the United Mitochondrial Disease Foundation, is pleased to announce it will grant a total of 179,000 USD to six research teams that are actively working toward improving diagnosis, developing treatments and optimizing clinical care for Leigh syndrome patients.

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More than 20 institutions answered the Consortium’s request for proposals seeking Leigh syndrome specific research that fell into one of two areas:

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1. Translational Research, defined as projects that contribute new tools for advancing basic research from the benchtop to the clinic, especially novel cellular and animal models or their application to deepen insights, biomarkers, diagnostics, or therapeutics for mitochondrial disease; and

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2. Clinical Research with a focus on patient-centered projects that 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; retrospective analyses on existing data sets or well-designed prospective analyses that will help inform the understanding of Leigh syndrome natural history; and/or projects that utilize existing outcome measures to assess disease progression as well as development of new clinically relevant outcome measures that can serve as endpoints for future clinical trials.

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An international scientific steering committee with deep expertise in Leigh syndrome conducted rigorous peer review on the research proposals submitted and chose six proposals to fund.  Scoring/review criteria included, but wasn’t limited to, responsiveness to the RFP, relevance to Leigh syndrome, scientific novelty, scientific premise and rigor, and potential to impact the lives of those affected with Leigh syndrome.  The awardees are:

Institution:    University of Pittsburgh

Applicant:     Michael Palladino

Project:         Novel dietary and pharmacological therapies in a Drosophila model of Maternally Inherited Leigh Syndrome

Award:          50,000 USD

Description: This submission is using fruit flies with the ATP6 mutation, representative of MILS (Maternally Inherited Leigh Syndrome) to study the therapeutic benefit of a ketogenic diet in identifying compounds,which increase neuromuscular performance and life expectancy. The ATP6 enzyme, also known as complex V in the electron transport chain, is crucial in making proteins for normal mitochondrial function. Mutations at this site will affect ATP production drastically, causing muscle degeneration and shorter life expectancy. It has been established that a ketogenic diet is highly effective in reducing neurological dysfunction and seizures in the MILS fly model. The efficacy of the diet, however, depends on the citric acid cycle, which is a precursor to the electron transport chain. This study proposes to expand the identification of essential metabolic compounds, found in the citric acid cycle, that are crucial to energy production and biosynthesis, and therefore improve neuromuscular function and lifespan.

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Institution:    Regents of the University of California

Applicant:     Gino Cortopassi

Project:         Fumarates for Leigh Syndrome

Award:          30,000 USD

Description: Fumarates are a class of molecules known to effectively improve mitochondrial function, however the types of fumarates investigated to-date have a limited ability to penetrate the brain, thus limiting their potential as therapeutics for LS patients. This proposal aims to explore the efficacy of an improved, more potent fumarate molecule known as IMF that also better permeates the brain. The investigators will use the NDufs4 mouse model to conduct dosing and endpoint experiments focused on improving mitochondrial function and extending lifespan. Success in this translational research project could lead to new clinical trials for LS patients in the future.

Institution:   Heinrich Heine University (HHU)

Applicant:    Alessandro Prigione

Project:         iPSC-driven repositioning of PDE5 inhibitors for Leigh syndrome patients carrying MT-ATP6 mutations

Award:          34,000 USD

Description: This study proposes to evaluate the efficacy of an established class of drugs for other indication in LS patients who have an MT-ATP6 mutation. MT-ATP6 mutations are one of the most common causes of LS. The investigators will use patient-derived stem cells to test PDE5 inhibitors as a targeted therapy capable of normalizing the neuronal defects caused by MT-ATP6 mutations. Successful data could lead to new clinical trials for LS patients.

Institution:    Wellcome Centre for Mitochondrial Research

Applicant:     Robert McFarland

Project:        Leigh syndrome: Investigating Outcome measure & Natural history (LION) - a prospective, longitudinal cohort study.

Award:          25,000 USD

Description: How a disease changes over time is called natural history. This submission proposes to run a natural history study of LS, utilizing validated patient and caregiver rating scales to quantify the burden of the disease over time. 50 children in total will be assessed at three time points over 24 weeks. After an initial baseline assessment, the scales will be administered every 12 weeks to monitor the progression of the disease.  The investigators expect that LS patients will have abnormally high rating scale scores even at baseline (reflective of the disease burden)and that the scores will increase over time as the disease progresses. Collecting natural history data in this manner will hopefully allow these clinical rating scales to serve as new clinical trial endpoints, a large need for the mitochondrial disease community.

Institution:   University of Iowa

Applicant:    Dao-Fu Dai

Project:        The role of microglia, NAD+ and mitochondrial ROS in Leigh Syndrome

Award:          15,000 USD

Description:  This project proposes to study the role of microglia (cells which mediate immune responses in the central nervous system (brain) in LS using the NDufs4 mouse model and neurons derived from patient stem cells. The hypothesis is that microglial activation contributes to LS and that inhibiting activation may have therapeutic benefit for LS patients. Using the models described above the investigators will test this hypothesis by altering microglial activation and seeing if it directly improves animal neuro-behavior or if a combination of microglial inhibition and NAD supplementation improves mitochondrial function and restores neuro-behavior.

Institution:   Fondazione Telethon

Applicant:    Brunella Franco

Project:         Therapeutic efficacy of miR-181a/b down regulation in Leigh syndrome

Award:          25,000 USD

Description: This submission proposes to validate how well a class of molecules in the cell called MicroRNAs (miRNAs) work in a commonly used LS mouse model called NDufs4. MicroRNAs, specifically MiR-181a/b, regulate cellular activity in the central nervous system (brain) and represent promising therapeutic tools that simultaneously modulate multiple biological pathways. Preliminary data showed miR-181a/b inactivation increases the survival rate of the Ndufs4 mouse. The researchers aim to further test this approach by injecting miRNA-181a/b into the LS mouse model and evaluate the animal’s behavior while running blood and tissue analyses in an effort to better understand how this pathway could provide protection to the brain.

"Since its inception, PALS’ mission has been to support meaningful research of this devastating disease," said Lori Martin, founder and president of PALS.  "Thanks to our generous supporters and Consortium partners, we’re thrilled to be able to jointly fund six projects that will help us better understand Leigh syndrome and hopefully lead us closer to a cure.”    

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The Leigh Syndrome International Consortium’s mission is to accelerate research aimed at uncovering better treatments and therapies for Leigh syndrome patients. Together, the Consortium has pledged more than 1 million USD to fund research with a focus on improving diagnosis, therapeutic development and optimized patient care for Leigh’s patients.  For additional information on the Consortium, visit www.leighsyndrome.org.  To learn more about PALS, visit www.peopleagainstleighs.org.