Funding the Next Generation

2021 accelerators Prize Winner

Lia Mayorga, MD, PhD

IHEM
Mendoza, Argentina

Modulation of the nuclear epigenome as a new strategy for mitochondrial DNA heteroplasmy shift
Project Summary

Human cells have two types of DNA, nuclear and mitochondrial DNA. The latter controls energy production for the body which is essential for life. Each cell has many mitochondria to generate sufficient energy for our organs, and inside each mitochondrion, there are many copies of mitochondrial DNA. In patients with certain types of mitochondrial diseases, the mitochondrial DNA copies are not identical, resulting in a mixture of defective and normal copies. The defective copies lead to poor mitochondrial function and disease, so the more defective vs. normal copies a cell has, the worse the disease symptoms. Our goal is to develop a method to selectively reduce the number of defective mitochondrial DNA copies, leaving mostly normal ones. Gene therapy strategies that have worked for nuclear DNA defects have not reached clinical trials for mitochondrial genes because the mitochondrion is very selective as to what can or cannot enter the organelle. We propose a different approach taking advantage of the cell’s natural communication between the nucleus and mitochondria. Previous work has shown that intense mitochondrial dysfunction, such as the one present in cells with mostly defective mitochondrial DNA, produces modifications to nuclear DNA (not in sequence, but in function) that perpetuate the survival of such unhealthy cells and sustain disease symptoms. Consequently, we plan to modify these nuclear DNA modifications that exist in dysfunctional cells to “select” cells with the less defective mitochondrial function. This nuclear DNA modulation technique is already used to treat other illnesses, which increases the possibility for it to reach clinical trials in less time.

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Innovation, speed and agility are key to finding effective treatments for mitochondrial disease.  Your support is the beginning.  Accelerating the research could lead to a cure.

Our accelerators are engaged philanthropists.  Through our annual livestream-pitch event, our members have the opportunity to cast their vote for the project they feel the most passionate about, and ultimately see the difference their contribution makes.

2021 accelerators Prize Finalists

Lia Mayorga, MD, PhD

IHEM
Mendoza, Argentina

Modulation of the nuclear epigenome as a new strategy for mitochondrial DNA heteroplasmy shift

Project Summary

Human cells have two types of DNA, nuclear and mitochondrial DNA. The latter controls energy production for the body which is essential for life. Each cell has many mitochondria to generate sufficient energy for our organs, and inside each mitochondrion, there are many copies of mitochondrial DNA. In patients with certain types of mitochondrial diseases, the mitochondrial DNA copies are not identical, resulting in a mixture of defective and normal copies. The defective copies lead to poor mitochondrial function and disease, so the more defective vs. normal copies a cell has, the worse the disease symptoms. Our goal is to develop a method to selectively reduce the number of defective mitochondrial DNA copies, leaving mostly normal ones. Gene therapy strategies that have worked for nuclear DNA defects have not reached clinical trials for mitochondrial genes because the mitochondrion is very selective as to what can or cannot enter the organelle. We propose a different approach taking advantage of the cell’s natural communication between the nucleus and mitochondria. Previous work has shown that intense mitochondrial dysfunction, such as the one present in cells with mostly defective mitochondrial DNA, produces modifications to nuclear DNA (not in sequence, but in function) that perpetuate the survival of such unhealthy cells and sustain disease symptoms. Consequently, we plan to modify these nuclear DNA modifications that exist in dysfunctional cells to “select” cells with the less defective mitochondrial function. This nuclear DNA modulation technique is already used to treat other illnesses, which increases the possibility for it to reach clinical trials in less time.

Michela Di Nottia, PhD

Bambino Gesù Children’s Hospital
Rome, Italy

The role of inflammation in diseases related to mitochondrial DNA maintenance: new potential biomarkers to be used as therapeutic targets

Project Summary

Mitochondrial diseases (MDs) are considered the most common inborn errors of metabolism causing a dysfunction in the energy production. The integrity of mitochondrial DNA (mtDNA) is important in producing healthy mitochondria, which is essential in the maintenance of cellular health. Damage to the mtDNA can induce a pro-inflammatory state in the cell. No studies to date, have addressed the link between innate immune response and mitochondrial function in primary mitochondrial diseases. My study proposes to explore the effect of mtDNA instability on inflammation and the clinical impact it has on affected patients. We will start studying Kearns-Sayre patients which are characterized by a single mtDNA deletion. We will evaluate inflammatory biomarkers in all tissue available (blood, muscle biopsy and cultured fibroblasts) and test the effects of appropriate drugs.
With this project we intend to elucidate novel relevant pathogenic pathways and to identify new potential biomarkers and therapeutic strategies to be tested in controlled clinical trials. Moreover, the results herein obtained will pave the way for the evaluation of the inflammatory status in other mitochondrial diseases, for which an early treatment could improve the clinical picture.

John Smolka, PhD

University of California, Berkeley
California, USA

Establishing roles for the mitochondrial tRNA biosynthetic machinery in mitochondrial genome maintenance

Project Summary
Mitochondria, the engines of our cells, contain their own small DNA blueprint, the mitochondrial genome, with genetic instructions important for our metabolism. Furthermore, our cells have to make hundreds to thousands of copies of the mitochondrial genome for normal health. Compared to our knowledge of how cells copy and pass on our non-mitochondrial DNA from cell to cell and parent to child, the mitochondrial DNA copying process, or mitochondrial DNA replication, is poorly understood. I am working to fully understand all the parts of the cellular machine that replicates mitochondrial DNA, and how they work. By reverse engineering the mitochondrial DNA replication machine, my work is uncovering the possibility that the genetic mutations that cause Mitochondrial Encephalopathy, Lactic-Acidosis and Stroke-like episodes (MELAS) do so by interfering with the mitochondrial DNA copying process. You cannot repair an engine unless you know how it works, and this fundamental knowledge has the potential to inform future therapeutic strategies for treating mitochondrial diseases that arise from MELAS-causing mutations and defects in mitochondrial DNA replication.

How It Works

UMDF earmarks the accelerators 
prize
($50,000 in 2021)
h

Grant applications submitted by promising post-doctoral fellows

 

Applications reviewed and finalists selected by UMDF Scientific and Medical Advisory Board

3-5 finalists prepare “fast pitches” to be broadcast live at UMDF Symposium

 

Z
Each accelerator 
casts a vote for the project they feel most passionate about

Prize awarded to winner

Right now… a researcher in a lab believes her theory could cure mitochondrial myopathy.

Right now… a scientist believes his innovation may bring about an end to Leigh syndrome.

Right now… people affected by mitochondrial disease need energy…and YOUR energy can help….but we need to go fast.

It could be an innovation that will find the cause of mitochondrial disease. Or, it may be the research that develops an effective treatment. Now is the time to accelerate that science from bench to bedside. Our patients and families are counting on your energy to help UMDF move faster toward a cure.

When you give $500 or more (cumulatively in a year), you unlock your accelerators benefits! No matter how you give – through a special event, to a designated fund or as a tribute to a patient – when you reach the accelerators level you join a group of engaged philanthropists. You will get a first-hand look at the promising ideas being developed in mitochondrial disease research.

In addition to the opportunity to jumpstart discovery for the next generation of mitochondrial disease researchers, our accelerators receive: 

  • Name recognition at the annual Symposium
  • accelerators lapel pin
  • accelerators social media badge

2020 accelerators Prize Winner

Kinsley Christopher Belle

Stanford University
Stanford, CA

Project Summary

Mutations in mitochondrial DNA result in an array of disease which can be found in nearly all tissue types of the human body. Furthermore, these mutations can exist in varying states of prevalence due to a rare phenomenon known as heteroplasmy. Heteroplasmy is the percentage of mutant mitochondrial DNA within a cell, tissue, or organ system.  The level of heteroplasmy or the percentage of mutation directly correlates with disease and cellular dysfunction. 

Our objective is to determine how internal factors, such as development and cell specification cues, as well as external stimulus, oxygen levels, energy substrates, and drug compounds influence mitochondria heteroplasmy. Our preliminary assessments suggest that cell-type development and cell division influence heteroplasmy in developing tissues, additionally our work on cell conditions, and small molecules has yielded promising preliminary results for possible therapeutics. This body of work serves as a template for discovering compounds that reduce mitochondrial heteroplasmy and thus disease burden in patients.

2019 accelerators Prize Winner

Arwen Gao

Ecole Polytechnique Federale de Lausanne (EPFL)
Lausanne, Switzerland

Project Summary

Dr. Gao was awarded a $50,000 prize for her project entitled Identification of Novel Compounds to Treat Rare Mitochondrial Diseases. The goal of this research project is to identify novel compounds that increase the amount of mitochondria and/or activate the identified pathway in lab-based cell models. The compounds that work best in the cell models will be subsequently tested in animal models of mitochondrial disease. Future work with top compound candidates have the potential to pave the way towards the development of novel drugs targeting rare mitochondrial diseases.

Scientists who are working fast toward a cure.

Vamsi K. Mootha, PhD

HARVARD MEDICAL SCHOOL • Boston, MA

“In 2004, I was a recipient of a $90,200 UMDF grant designed to support my efforts on using computational genomics to identify novel assembly factors for mitochondrial oxidative phosphorylation. With this support, I was able to recruit and hire a talented computational biologist, who proceeded to predict the mitochondrial proteome using a computational tool that led to the identification of several new disease genes, forming the basis for my lab’s first NIH grant.”

Anna-Kaisa Niemi MD, PhD

RADY CHILDREN’S HOSPITAL • San Diego, CA

“A UMDF Clinical Fellowship Award allowed me to focus on diagnosis and treatment of patients with confirmed or suspected mitochondrial disorders. The most impactful part of the fellowship for me was learning about the daily life of children and families affected by mitochondrial disorders. I now continue to use the knowledge and experience I gained that year in my work caring for critically ill infants with confirmed or suspected mitochondrial disorders.”

Michael J. Palladino, PhD

UNIVERSITY OF PITTSBURGH • Pittsburgh, PA

“In 2006, I received a $98,000 research grant from UMDF. This grant funded my research to further develop our Drosophila NARP/MILS model and allow our first venture into compound screening to identify specific drug therapies for mito patients. This award served as “bootstrap funding” helping me successfully apply to the NIH for support of numerous projects and helped secure more than $2.75M in NIH funding for mito research in my lab.”

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