Research

This nonprofit entity is developing a visionary and innovative approach to treat and cure complex mitochondrial diseases. The Foundation aims to be a leading funder of basic, translational and clinical PolG research. Working with the global scientific community, we are investing in developing critical tools. We continue to make our findings available to mitochondrial scientists, clinicians and patients worldwide.

PROJECTS

Mouse Model Project 1*

Generating and investigating in vivo PolG mouse models to unravel the mechanistic pathogenesis of PolG disorders.

RESEARCH DATE: JUNE 2021 - ONGOING

Maria Falkenberg is a professor of medical biochemistry at the University of Gothenburg. She is a leading expert in mitochondrial DNA replication with 25 years of experience in medical biochemistry. Her laboratory studies mitochondrial DNA polymerase (PolG) and how disease-causing mutations in this protein disturb normal mitochondrial function. Her work has been published in journals such as Nature, Molecular Cell and Proc. Natl. Acad. Sci. USA. Maria is a member of the Royal Swedish Academy of Sciences. She holds a Ph.D. in medical biochemistry from the University of Gothenburg and performed 2.5 years of undergraduate training at the Stanford University School of Medicine. She was a postdoctoral fellow at the Karolinska Institutet.

Claes Gustafsson is a professor of medical biochemistry at the University of Gothenburg and is a leading expert in mitochondrial gene expression and replication with 30 years of experience in medical biochemistry. His laboratory investigates various aspects of mitochondrial molecular genetics, including extensive work to understand the links between mitochondrial DNA polymerase (PolG) function and mitochondrial gene expression. His expansive work has been published in journals such as Nature, Cell and Molecular Cell. Claes is a member of the Royal Swedish Academy of Sciences. He holds an M.D. and Ph.D. in medical biochemistry from the University of Gothenburg and conducted postdoctoral training at the Stanford University School of Medicine.

Nils-Göran Larsson is a professor of mitochondrial genetics at the Department of Medical Biochemistry and Biophysics at the Karolinska Institutet. He has specialized in mitochondrial biology for more than 30 years and is a pediatrician and a senior consultant at the Centre for Inherited Metabolic Diseases at Karolinska University Hospital. He has used genetics to decipher the importance of mitochondrial DNA polymerase (PolG) function in mammalian development, ageing and disease. He has published over 150 articles on mitochondrial biology, including features in Nature, Cell, Cell Metabolism and the Annual Review of Biochemistry. He is a member of the Swedish Royal Academy of Sciences and EMBO. Nils holds an M.D. and a Ph.D. in mitochondrial genetics from the University of Gothenburg and conducted postdoctoral training at the Stanford University School of Medicine.

Carlo Viscomi is associate professor of biomedical sciences at the Università di Padova. In his work, he has explored numerous strategies to fight mitochondrial diseases and in recent work, Carlo has established the first mouse models for disease-causing mutations in the mitochondrial DNA polymerase (PolG). These models are now used to understand disease progression and probe ways to cure affected patients. Carlo’s work can be found published in journals such as Nature Medicine, Nucleic Acids Res. and EMBO Molecular Medicine. He holds a Ph.D. in physiology from the University of Milano and conducted postdoctoral training at the I.R.C.C.S. Istituto Neurologico C.Besta in Milano.

Massimo Zeviani is professor of neurology at the Università di Padova and group leader at the Veneto Institute for Molecular Medicine, Padova, Italy. His research group has discovered a huge number of disease mutations in mitochondrial DNA polymerase (PolG) and investigated the underlying, disease-causing mechanisms, with the ultimate goal of finding ways to cure affected patients. He is also working towards establishing a center of excellence for high-throughput, precision medicine to study patients, particularly children, with mitochondrial disease from the clinical, biochemical and genetic standpoints. Massimo’s work can be found published in journals such as Nature, Nature Genetics, Lancet and Cell Metabolism. He holds an M.D. from Università di Padova and a Ph.D. from Université de Paris Descartes.

Mouse Model Project 2*

Development and preclinical validation in mice of a gene therapy treatment for PolG disease.

RESEARCH DATE: SEPTEMBER 2021 - ONGOING

Cat Lutz is the Senior Director of the Rare and Orphan Disease Center as well as the In Vivo Pharmacology and Drug Efficacy Testing Service. She serves as the principal investigator/co-investigator of multiple NIH-sponsored programs, including the Center for Precision Genetics, The Somatic Cell Genome Editing program and the Mutant Mouse Resource and Research Center (MMRRC). Dr. Lutz has over 30 years of experience in mouse genetics, with a primary focus on modeling human disease and seeking therapies for rare diseases, such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Dr. Lutz was recently awarded the 2021 Rare Impact Award by the National Organization for Rare Disorders (NORD).

Metodi Metodiev works at the Imagine Institute for Genetic Diseases in Paris, France and is a permanent research associate with the French National Institute of Health and Medical Research (INSERM). Metodi received his Ph.D. from the University of Cologne, Germany where he studied the regulation of proteolysis in yeast and mammalian mitochondria. He did his postdoctoral research at the Karolinska Institutet in Stockholm, Sweden and the Max Planck Institute for Biology of Aging in Cologne. These early career experiences cultivated in him a strong desire to apply his knowledge and skill set to the field of mitochondrial medicine. Therefore in 2013, Metodi joined the Imagine Institute for Genetic Diseases, where he has since been using cellular and mouse models of mitochondrial dysfunction to understand the pathophysiology of mitochondrial diseases. His ultimate goal is to apply this understanding to the development of efficient treatments for these devastating and currently incurable pathologies.

Since 1979, Arnold Munnich has dedicated his life to the identification of genes responsible for neurological, metabolic, malformed and sensorial handicaps in children. The M.D., Ph.D., researcher and author has served as Professor of Genetics at Université de Paris Descartes and directed the Inserm unit "Genetic handicaps of the child" at Necker– Enfants Malades Hospital, where he helped found the Imagine Institute (Institut des Maladies Génétiques). A member of the French Academy of Sciences since 2004, Professor Munnich served as biomedical and health research advisor to French President Nicolas Sarközy from 2008-2012 and in 2014, received the Grand Prize of the City of Paris for Medical Research and was awarded the Légion d’Honneur. His prize-winning work has turned genetic research into practical applications for the treatment and care of people battling genetic handicaps, as well as their families.

Dr. Steve Murray has nearly 20 years of experience developing and studying mouse models of disease, including congenital malformations and other rare diseases. Much of his program focuses on the large-scale generation of mouse genetic resources for the greater scientific community, including the Knockout Mouse Phenotyping Program, which aims to interrogate gene function through the systematic deletion of every gene in the genome and to characterize the outcomes in mice. His research focus includes the development and application of new technologies and methods to model rare disease mutations in mice. He is one of the principal investigators of the JAX Center for Precision Genetics at The Jackson Laboratory, which aims to build new models for rare disease with the goal of advancing therapeutic strategies and he leads a core component of the Somatic Cell Genome Editing Consortium, a large, multi-investigator effort to accelerate the use of genome editing technology for therapeutic benefit. He earned his Ph.D. from Boston University School of Medicine and did his postdoctoral training at The Jackson Laboratory.

Agnès Rötig is the research director (DR1, INSERM) of the Imagine Institute. She completed her Ph.D. in mitochondrial biology at Université Pierre et Marie Curie. She did postdoctoral training in INSERM U12 at Hôpital Necker Enfants Malades, during which she built her research group in the field of mitochondrial disorders in close collaboration with the Genetics Unit of Hôpital Necker Enfants Malades. By using gene mapping, candidate gene analysis and now next generation sequencing, she has described several novel genes responsible for these disorders.

Benedetta Ruzzenente is a permanent research associate with the French National Institute of Health and Medical Research (INSERM), working at the Imagine Institute for Genetic Diseases in Paris, France. Benedetta received her Ph.D. from the Universita di Padova (Italy), where she studied the regulation of mitochondrial and cytosolic deoxyribonucleotide pools. Her postdoctoral research took place first at the Karolinska Institutet (Stockholm, Sweden) and then at the Max Planck Institute (Cologne, Germany) where she studied the molecular mechanisms regulating mitochondrial gene expression using mouse genetics. In 2015, she joined the Genetics of Mitochondrial Disorders unit at the Imagine Institute with the goal of understanding the molecular mechanism of mitochondrial diseases and developing treatments for these conditions.

As the leading European center for research, care and education on genetic diseases, Imagine’s goal is to change the lives of families affected by genetic diseases. To achieve this goal, Imagine focuses on four major areas: research, innovative care, education and promotion. At Imagine, patients with genetic diseases are at the heart of the virtuous circle. Created by the Institute’s founders, this circle begins with the patient and finishes by curing the patient or at least relieving their suffering. Imagine brings together in one building all the skills and expertise necessary to accelerate research, develop innovative care and generate synergies and conditions to drive innovation.

Here at The Jackson Laboratory (JAX), our team of nearly 3,000 people are working toward one goal — to discover precise genomic solutions for disease and empower the global biomedical community in our shared quest to improve human health. JAX is a world leader in mammalian genetics and human genomics research. Founded in 1929 in Bar Harbor, Maine, The Jackson Laboratory is an independent, nonprofit research institution with locations in Maine, Connecticut, California, Japan and China.

A Systematic Review of Animal and Cell Models of PolG Disease*

RESEARCH DATE: SEPTEMBER 2020 - AUGUST 2021

Download PDF Report >

Complete systematic review awaiting publishing.

Wellcome Centre for Mitochondrial Research & The Lily Foundation

PolG, also known as the mitochondrial polymerase g (gamma), is an enzyme crucial to the production of mitochondrial DNA (mtDNA). In humans, errors in the POLG1 gene cause this polymerase g enzyme to malfunction and lead to a range of debilitating diseases in which people typically have a reduced amount or quality of mtDNA. This depletion of mtDNA can lead to impaired energy generation in many body tissues, but particularly the brain, muscle and liver.

The main aim of this project was to complete a review of the published scientific literature to improve our understanding of PolG disease. The review was guided by clinical assessment of a male aged 18 years (Patient F) who was seen by the clinical team in Newcastle in December 2020. Patient F harbors two genetic mistakes within POLG1. Polymerase g is the only enzyme responsible for replication of the mitochondrial genome and so it is not surprising that mutations in POLG1 are responsible for mitochondrial DNA (mtDNA) defects. As well as the depletion of mtDNA described above, this can also include an accumulation of mtDNA deletions and point mutations.

The project, led by Dr. Nichola Lax from the Wellcome Trust Centre for Mitochondrial Research (WCMR) at Newcastle University and with MRes student John Meyrick, produced two reviews that focused on two main areas: (1) specific medical problems associated with PolG disease and (2) laboratory model systems of PolG disease. A brief overview is provided below:


Review 1):
Following consensus agreement, the clinical symptoms of PolG disease selected for further investigation in the scientific literature included peripheral neuropathy, myoclonus and achalasia. The review provides further information on the prevalence, etiology and current treatments for these particular medical problems and identifies areas requiring further basic and clinical research.


Review 2):
Animal and cellular models are pivotal to further our understanding of PolG disease and inform treatment development. The systematic review provides details of the disease models used in research and evaluates their effectiveness in recapitulating the clinical and molecular genetic features of PolG disease. It is hoped that both reviews provide the important groundwork to direct future research aimed at developing and improving treatment options for PolG disease, with the ultimate aim of finding a cure.

Professor Gráinne Gorman qualified from the Royal College of Surgeons in Ireland (RCSI) in 1997 and completed three years of general medical training in Dublin, Ireland. She became medical tutor for third and final medical year students at RCSI for one year, prior to commencing her clinical training in neurology. After completion of this specialist training, she moved to Newcastle to further her interest in neuromuscular diseases and was appointed Honorary Consultant Neurologist at Newcastle upon Tyne Hospitals NHS Foundation Trust in 2010. She completed her PhD studies investigating the clinical and genotypic aspects of mitochondrial disease in 2015 and became Senior Clinical Lecturer at Newcastle University the following year. Gráinne was promoted to Professor of Neurology in 2020 and at the same time appointed Director of the Wellcome Centre for Mitochondrial Research (WCMR) at Newcastle University, where she continues to work with colleagues to strengthen the reputation of the WCMR as an internationally renowned centre of excellence in mitochondrial disease and dysfunction. To achieve this, she is committed to attracting, developing and retaining a diverse and inclusive team of outstanding scientists whilst also promoting creativity, encouraging resilience and equipping the next generation of academics to become global leaders at the forefront of medical breakthroughs. Her other leadership roles include the NIHR BRC Lead for Mitochondrial Disease and Lead of the Mitochondria and Neuromuscular Theme within the Newcastle University Translational and Clinical Research Institute, which have all benefited from her successful recruitment to The Academy of Medical Sciences FLIER leadership programme (acmedsci.ac.uk).

Dr. Nichola Lax is a postdoctoral researcher within the Wellcome Trust Centre for Mitochondrial Research at Newcastle University. She first became interested in the impact of mitochondria dysfunction on the central and peripheral nervous systems when she joined the Centre in 2007 to begin her Ph.D. studies. She now leads a research program which aims to identify the molecular mechanisms contributing to neurodegeneration and neurological decline in patients with mitochondrial disease. Together with her colleagues, she has helped develop a unique repository of human post-mortem brain tissues from patients with clinically and genetically well-defined mitochondrial disease within the Newcastle Brain Tissue Resource. This represents the largest (>60 brains) collection internationally and has provided crucial insights into the neuropathological features associated with various neurological conditions in mitochondrial disease. One particular focus has been understanding medically refractory epilepsy associated with mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS) and PolG-related disease. Her neuropathological insights have been instrumental for developing a transgenic mouse model which recapitulates features of epilepsy and selective neuronal vulnerabilities associated with mitochondrial dysfunction. This work will enable identification of disease mechanisms and will inform development of therapeutic targets to improve patient care and treatment.

Professor Bobby McFarland trained in pediatrics and pediatric neurology in London and Newcastle upon Tyne. He began his research career studying the molecular consequences and clinical problems associated with mutations of mitochondrial DNA. Bobby’s research now embraces gene discovery, determinants of pathogenicity in mitochondrial disease and clinical research projects including the development of clinical assessment tools, natural history studies, outcome measures and drug trials. As Director of the NHS Highly Specialised Service for Rare Mitochondrial Disorders, Bobby leads a team of clinicians, nurses and allied health professionals dedicated to the diagnosis and management of mitochondrial disease. The close association of Bobby’s research and clinical work pays dividends for both, facilitating recruitment to the extremely successful national Mitochondrial Patient Cohort study (n=1850), which he leads and allowing rapid translation of research breakthroughs into clinical practice such as the groundbreaking IVF technique of mitochondrial replacement therapy (MRT), where Bobby has leveraged Wellcome and NHS funding to offer a clinical research program. Bobby is currently Professor of Pediatric Mitochondrial Medicine and Action Medical Research Professor of Neuromuscular Disease at the Wellcome Centre for Mitochondrial Research at Newcastle University.

The Wellcome Centre for Mitochondrial Research is built on our long standing clinical and scientific expertise in mitochondrial disease. We are totally committed to providing the best care for our patients and this means that we must understand more about the mechanisms underlying mitochondrial disease. If we are to develop new strategies for preventing or treating mitochondrial disease, it is fundamentally dependent upon very high quality research.

The Lily Foundation is the UK's leading charity dedicated to fighting mitochondrial disease. Their mission is to support people whose lives are affected by the condition, raise awareness and fund research into its prevention, diagnosis and treatment. The charity is run by a small team of dedicated staff and volunteers and they are backed by a medical board drawn from the UK's top centers of mitochondrial research and clinical care. The Lily Foundation forms a vital international link between patients, doctors and medical science organizations.

*Research initiated by the Co-Founders, prior to the incorporation of the POLG Foundation, to jump start the urgent work of the Foundation.