Research

Funded Projects

Mitochondrial genome editing for Pearson marrow pancreas syndrome

Principal Investigator:
Suneet Agarwal, MD, PHD
Institution/Division:
Boston Children's Hospital/Hematology-Oncology
Direct Cost Requested
$100,000
Lay Abstract:
A number of diseases are caused by dysfunction of the mitochondria, which are organelles in our cells that supply energy and perform other vital functions. Mitochondria contain many copies of their own genetic material (mtDNA), which encodes proteins critical for energy production. In mitochondrial genetic diseases, children are born with mutations in some copies of their mtDNA, resulting in dysfunction of a variety of organs that fluctuates throughout life. For example, in the mtDNA deletion disorder Pearson marrow pancreas syndrome (PS), children are born with severe blood disease and frequently digestive disorders, hormonal disturbances, and kidney problems. If children survive, they may go on to develop heart, muscle and nervous system disease as teens or young adults. For PS and other mtDNA disorders, therapy is supportive and there are no cures. A suggestion for how to tackle PS comes from observations of changes in the mtDNA in the patients themselves. Their mitochondria contain mixtures of normal and mutant mtDNA (called heteroplasmy), and over time, the ratio of mutant to normal mtDNA fluctuates in different tissues and correlates with disease. In laboratory studies, PS patient cells that are grown in a dish also show changes in the ratio of mutant to normal mtDNA over time. If we can understand this fluctuation better, and to think of ways to push the ratio in the direction of normal mtDNA in cells, we may be able to translate these insights and create new therapies for patients with PS. In this proposal, we aim to innovate and apply novel approaches to specifically deplete mutant mtDNA in PS patient cells. Our goal for this research project is to develop the tools and knowledge needed to develop a targeted therapy for patients with PS and related mtDNA disease.

Treatments and models for diseases caused by mitochondrial deletions

Principal Investigators:
Michal Minczuk and Payam Gammage
Institution/Division:
University of Cambridge
Direct Cost Requested
$100,000 over two years
Lay Abstract:
Mitochondria are cellular structures that provide energy from food that cells can use. They also contain DNA, called mtDNA. Intact mtDNA is vital for healthy functioning of the cell. Genetic mutations in mtDNA, where a single DNA building block is changed, or a part of mtDNA is deleted, can lead to human diseases, often affecting brain, heart, bone marrow and muscles. There are no treatments for these diseases. Our approach to treatment of mtDNA diseases is to design proteins that can specifically eliminate only the mutated mtDNA, curing patients’ cells. We have already achieved this goal using in vitro models of mtDNA disease. The essential next step in bringing these proteins to the clinic is to test them in the types of cells that are affected in patients (neurons, muscle cells or blood cells) and in a living organism (in vivo). Therefore, in the first part of the proposed research, it is our intention to generate neurons, muscle cells or blood cells from patient skin cells that lack a fragment of mtDNA, into which we will administer therapeutic proteins. We expect that our intervention will improve the function of these cells, providing important pre-clinical data on the safety and efficacy of our approach. In the second part of of our planned research, we intend to develop a DNA-editing tool enabling us to cut out mtDNA fragments at will. Such a tool could be used in the future to produce animals with deleted mtDNA that would develop disease symptoms similar to human patients. These model organisms can be used to further test our therapeutic proteins and other drugs, providing the vital pre-clinical data required to take the next steps towards the use of experimental therapeutic strategies in humans.

CD34+ cells enriched with blood cells derived healthy mitochondria as a treatment for Pearson Syndrome

Principal Investigators:
Amos Toren, Natalie Yivgi Ohana, Elad Jacoby, Ann Saada
Institution/Division:
Sheba Medical Center
Direct Cost Requested
$130,000 over one year
Lay Abstract:
A collaboration between hematologists from Sheba Medical Center (Prof. Amos Toren and Dr. Elad Jacoby), mitochondria-scientist from Hadassah-Hebrew University Medical Center (Prof. Ann Saada) and a researcher from a biotechnology company in Israel (Dr. Natalie Yivgi Ohana) has created a scientific research plan to bring a novel therapeutic approach to Pearson Syndrome. The technology, developed by Minovia Therapeutics over the past 6 years, is based on transplantation of normal mitochondria in patient’s stem cells.  The patient’s own bone-marrow cells would be carriers of normal mitochondria from a donor (without deletions) and would carry normal mitochondria to other tissues through the blood stream. The group will first conduct animal studies to show the effect of such treatment on mice harboring a mitochondrial DNA mutation and use the results to apply to the FDA for a formal clinical trial.