Development of a novel therapy for muscle weakness in patients with mtDNA deletions using autologous, boosted, mutation-free mesoangioblasts
- Principal Investigators:
- Dr. Bert Smeets
- Institution/Division:
- University of Maastricht
- Direct Cost Requested:
- $35,265 over 1 year
- Date Awarded:
- November 2020
- Lay Abstract:
-
In SLMDS, muscle weakness is an important, progressive debilitating feature for
which no effective therapy is currently available. In this project, we will
develop a novel therapeutic strategy by inducing muscle regeneration through the
administration of large numbers of healthy, autologous muscle stem cells, called
mesoangioblasts to the patient's blood. These mesoangioblasts migrate to affected
muscles, grow into healthy muscle fibers and compensate loss of muscle strength. In a
preliminary study, we have demonstrated that all CPEO patients with an mtDNA deletion
have exclusively mutation-free, wild-type mesoangioblasts, despite high mtDNA deletion
loads in muscle, and can be directly used for treatment. In this project we will extend this
to Pearson and KSS patients and test if their mesoangioblasts are similarly comparable to
healthy controls. As we have established a culturing protocol for mesoangioblasts,
according to Good Manufacturing Practice (GMP), we will design a Phase II clinical
trial, once safety of the treatment has been established in an ongoing Phase I/II trial. To
improve our therapeutic strategy, we will also boost the mitochondrial content of the
mesoangioblasts in order to more effectively increase the number of wild-type mtDNA in
the muscle of mtDNA mutation carriers.
A screen of FDA-approved drugs that are mitophagy modulators to identify therapies for single large-scale mtDNA deletion disorders
- Principal Investigators:
- Dr. Suraiya Haroon and Dr. Marni Falk
- Institution/Division:
- Children's Hospital of Philadelphia
- Direct Cost Requested:
- $97,504.96 over 2 years
- Date Awarded:
- December 2020
- Lay Abstract:
-
Mitochondria are components of our cells that are so specialized to
make the energy we need to live that they their own DNA in order to streamline the
production of energy. The genes in the mitochondrial genome (mtDNA) code for
proteins essential in energy production and thus, maintaining the integrity of the
mitochondrial genome is essential for human health. It is well-documented that
single large deletions in the mitochondrial genome are pathogenic and can give rise
to various diseases characterized by neuromuscular dysfunction such as Pearson's
Syndrome and Kearn's Sayre Syndrome. Currently there are no FDA-approved cures
or treatments for mitochondrial diseases. We will address this hurdle by taking two
approaches to identify therapies using the microscopic worm model C. elegans.
These worms are amenable to genetic and pharmacological manipulation, cost-
effective and easy to rear. Most importantly, there already exists a strain that carries
a single-large mtDNA deletion and such a mutant strain does not exist for any other
model organism. Using this strain, we will first exploit the mechanism of mitophagy,
the process by which dysfunctional mitochondria are degraded, in order to develop
therapies. There are numerous publications showing that modulating mitophagy
can impact mitochondrial disease progression and we will build on this knowledge
to help develop targeted therapy for large-scale single mtDNA deletion diseases.
Second, we will conduct a drug screen on 2560 FDA-approved and natural
compound library to identify potential therapeutics. Any therapies identified to
ameliorate the mutant worms using either avenues of inquiry will be validated in
human patient cell lines. As an added benefit, since most compounds in the library is
already considered safe for human consumption by the FDA, if some of them are
able to rescue mitochondrial disease, these compounds can become available to
patients more rapidly than novel compounds untested for human use.
Towards genome-wide screens to identify new drug targets in single large-scale mtDNA deletion syndromes
- Principal Investigators:
- Suneet Agarwal, MD, PHD
- Institution/Division:
- Boston Children's Hospital/Hematology-Oncology
- Direct Cost Requested:
- $100,000
- Date Awarded:
- July 2020
- Lay Abstract:
-
Mitochondria are structures in our cells that perform numerous critical functions,
including serving as the cell's energy production source or powerhouse. Unique among
other structures in the cell, mitochondria have their own genome, called mitochondrial
DNA (mtDNA). In a number of rare genetic diseases, there are mutations in mtDNA,
resulting in defects in mitochondrial function, failure of cells and organs, and
ultimately sickness and death. There are no effective therapies for mtDNA diseases.
In single large-scale mtDNA deletion (SLSMD) disorders, such as Pearson syndrome and
Kearns-Sayre syndrome, large segments of mtDNA are missing in some genomes,
intermingled with normal mtDNA. In some cell types, we can see a shift in the balance
of mutant to normal mtDNA over time, which correlates with disease improvement. In
this study we aim to understand how the proportion of mutant mtDNA versus normal mtDNA
can be shifted. Specifically, our proposal aims to develop new ways to 'count' mutant
mtDNA in PS patient cells reliably. Such a tool would lead us to apply thousands of
different treatments to PS cells and identify which of these will eliminate mutant
mtDNA. If successful, these studies are expected to lead to new treatments for PS and
a range of mitochondrial disorders.
Targeting cellular pathways disrupted in Pearson marrow pancreas syndrome
- Principal Investigators:
- Suneet Agarwal, MD, PHD
- Institution/Division:
- Boston Children's Hospital/Hematology-Oncology
- Direct Cost Requested:
- $100,000
- Date Awarded:
- February 2019
- Lay Abstract:
-
Pearson syndrome (PS) affects multiple parts of the body over the lifespan. This poses
a major challenge in developing genetic and cellular treatments, in terms of delivery
to all the organs and tissues. Another problem with genetic therapies is a need to
customize to the specific mutations in question. To address these barriers, we aim to
develop strategies that will work throughout the body in PS patients, irrespective of
the mutation. We will lay the foundation for these efforts under this grant by
identifying pathways in cells that are commonly disrupted due to mitochondrial DNA
(mtDNA) deletions. We will use PS patient cells and newly developed technologies that
will enable us to analyze the effects of mtDNA deletions on cellular functions, at a
previously unobtainable resolution. We expect that these studies, if successful, will
provide new targets to develop systemic treatments for PS.
Developing a gene therapy approach to treat mtDNA deletion syndromes
- Principal Investigators:
- Carlos Moraes
- Institution/Division:
- University of Miami
- Direct Cost Requested:
- $100,000 over 2 years
- Date Awarded:
- July 2018
- Lay Abstract:
-
We propose to develop a new class of mitochondrial-targeted DNA editing enzyme to
eliminate mtDNA harboring large rearrangements. This new architecture, named
mitoMeganuclease will cleave the mutant mtDNA allowing the wild-type to repopulate the
cells. The second aim is to produce a mouse model of mtDNA deletions. We will transfer
deleted mtDNA from cultured cells into mouse ES cells and produce females harboring
mtDNA deletions. We will attempt to transmit these deletions through the germline.
These two aims, if successful will advance the treatment of disease caused by mtDNA
deletions.
Promoting clinical development of Mitochondrial Augmentation Therapy for Pearson Syndrome Patients
- Principal Investigators:
- Amos Toren, Elad Jacoby, Natalie Yivgi Ohana, Noa Sher, Moriya Blumkin
- Institution/Division:
- Sheba Medical Center, Israel
- Direct Cost Requested:
- $125,000 over 1 year
- Date Awarded:
- July 2018
- Lay Abstract:
-
Our research and others have shown that healthy mitochondria can enter cells with
damaged mitochondria and repair their function. Our preliminary results with several
Pearson Syndrome patients demonstrate that healthy mitochondria taken from mothers can
enter patient-derived blood cells and reduce symptoms related to Pearson Syndrome. We
wish to advance this treatment to an FDA-cleared clinical trial, by providing
preclinical proof that healthy mitochondria can rescue bone marrow function in mice.
We also aim to optimize the system currently used to process patient samples. Finally,
we will perform various tests of patient samples to identify possible markers that may
correlate with clinical efficacy. Together, the results from funding will enable
commencement of a clinical trial with optimal equipment, and provide a deeper
understanding of treatment efficacy.
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, Israel
- Direct Cost Requested:
- $130,000 over 1 year
- Date Awarded:
- April 2017
- 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.
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 2 years
- Date Awarded:
- April 2017
- 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.
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
- Date Awarded:
- February 2016
- 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.