Gene Editing Takes Aim at Mitochondrial Disease
Summary
- A new gene editing method aims to correct certain mutations in the DNA of mitochondria, which are major producers of energy in the body.
- A study led by neuroscientist and Sylvester researcher Carlos Moraes, Ph.D., showed that this method is effective in a model of mitochondrial disease.
- Ongoing experiments to improve the approach may lead to new ways to treat similar diseases in people.
A new gene editing study offers a glimmer of hope for people with diseases that affect the powerhouse of the cell – the mitochondria.
These little cellular components produce much of the body’s energy. They are encased in their own membrane and have their own DNA, which is susceptible to disease-causing mutations.
Scientists have now corrected one such mutation in a preclinical disease model, bringing researchers a step closer to treating similar mitochondrial diseases in people.
That is a long-term aim of study leader Carlos Moraes, Ph.D., a neuroscience researcher at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.
“I want to find an approach that can be used in patients,” said Dr. Moraes, who is also a professor of neurology at the Miller School.
“Dr. Moraes and colleagues are making progress towards the goal of successfully treating patients with mitochondrial disease, who currently lack effective therapies,” said David Lombard, M.D., Ph.D., co-leader of Sylvester’s Cancer Epigenetics Program and clinical professor of pathology and laboratory medicine at the Miller School, who was also involved in the study.
The findings were published Jan. 29 in Science Translational Medicine.
Base Editing Basics
Most mitochondrial diseases are caused by mutations in mitochondrial DNA. Symptoms range from muscle weakness and exercise intolerance to heart, brain, hearing and vision problems. Treatments are largely palliative. There are no cures.
To attempt to correct mitochondrial DNA mutations, Dr. Moraes and his team harnessed a new approach that leverages a technique called base editing.
Base editors take aim at the four key molecular modules of DNA, the bases A, G, C and T. The new base editing method changes a C into a T and was previously found to correct certain mitochondrial DNA mutations in cell-based experiments.
Dr. Moraes and his colleagues went a step further and applied the technique to a model of disease.
Course Correction: Targeting the Mitochondrial Genome
The researchers targeted the base editing machinery to a specific portion of the mitochondrial genome, mainly in heart and muscle tissue. Delivery to these tissues was accomplished by linking the editing machinery to a benign, virus-like particle designed to home to them.
The method was able to correct the function of the mutated gene, which is important for mitochondrial energy production.
Biomarker analysis in Dr. Lombard’s lab of a key metabolite, lactate, also suggested the method improved heart function.
The researchers, however, found that increasing the dose of the base editor resulted in an increase in unwanted C-to-T editing in other regions of the mitochondrial genome.
“We have a word of caution here. If you increase the concentration of the base editor, it starts to be less specific, and you start to hit other positions,” said Dr. Moraes.
This effect limits the use of the technique in humans, at least for now.
Dr. Moraes is conducting experiments to prevent the unwanted DNA damage and extend the technique to other mutated genes. Newer base editors are more specific for the target, and yet others can change additional bases.
Dr. Moraes and his colleagues have also helped develop a separate technique designed to eliminate, rather than edit, the mutated mitochondrial DNA. That technique is being moved forward by the biotechnology company Precision BioSciences, which may initiate a clinical trial as early as this year.
Cancer Connection
An estimated 9.6 per 100,000 people are affected by diseases caused by mutations in mitochondrial DNA.
The findings may have even broader, longer-term implications for health. Mitochondrial defects accumulate with age. They are also known to promote cancer, for instance, by affecting metabolism and the production of “epigenetic” regulators that control gene activity.
“Mitochondrial function is deeply interconnected with our well-being,” said Jose “Pepe” Barrera Paez, a graduate student in Dr. Moraes’ lab and first author of the study.
Anthony Griswold, Ph.D., associate director of the Center for Genome Technology at the John P. Hussman Institute for Human Genomics at the Miller School, is also involved. Dr. Griswold conducted the genetic analysis of the efficiency and off-target effects of the method.
“This was a team science project with the potential of having real therapeutic implications down the line,” said Dr. Griswold.
Tags: cancer research, Center for Genome Technology, Dr. Anthony Griswold, Dr. Carlos Moraes, gene editing, genome editing, Hussman Institute for Human Genomics, mitochondrial diseases, mutant mitochondrial DNA, Sylvester Comprehensive Cancer Center