MT-ATP6 Leigh Syndrome Research
MT-ATP6 UPDATE 2024
Meet the Team
Texas, USA
Team Dr. Gray, Dr. Ling, and company are based in the UT Southwestern Medical Center, Texas, USA. They were granted significant funds from the National Institute of Health to develop an ATP6 gene replacement therapy with adeno-associated virus. This therapy aims to reduce the mutation heteroplasmy, possibly below the pathogenic levels, thus significantly improving the health and longevity of our children.
Cambridge, United Kingdom
Team Dr. Michal Minczuk and company are based at the University of Cambridge, UK. Their research aims to develop a mouse model for the ATP6 Leigh Syndrome. The mice will be a test bed for the gene replacement therapy Dr. Gray's lab develops. This makes Dr. Minczuk's work of crucial importance for the success of our mission. He and his team are also developing alternative gene therapy for a few specific MT-ATP6 point mutations. Dr. Minczuk is being funded by the Cure ATP6 campaign.
2023 Progress
- Mouse model with MT-ATP6 m.8069G>A mutation is developed using based editing technology.
- A few generations of that mouse model are grown, and a heteroplasmy level of about 70% is achieved.
- A technology called “Heteroplasmy shifting” is developed. It aims at eliminating defective mitochondria in favor of healthy ones. This way, the heteroplasmy level is reduced, and the energy production is increased. Successful experiments with m.8993T>G and m.5024C>T mutations are conducted.
- Gene base editing is developed for three specific ATP6 mutations 8993T>C, 9176T>C, and 9185T>C.
Future work
- Characterization of the MT-Atp6 mouse by performing many lab tests.
- To analyze how precise is the m.8993T>C correction
- To correct m.8993T>C in organoids (with Alessandro’s lab)
- To correct m.9176T>C in cells and progress towards the organoid work
- To correct m.9185T>C – material being gathered
Dusseldorf, Germany
Team Dr. Alessandro Prigione and company are based in the Heinrich Heine University, Dusseldorf, Germany. Based on patient-derived stem cells, they grow neuronal tissues and even mini-brains in a dish. Their lab produces miniature brains with ATP6 Leigh Syndrome that can be used to test gene therapies developed by the other labs (Drs. Gray, Ling, and Minczuk). Besides, the tissues produced by Dr. Prigione's lab will be used for massive screening to find existing drugs that can positively impact our children. Cure ATP6 campaign is also funding Dr. Prigione's lab.
2023 Progress
- Induced pluripotent stem cells are derived from ATP6 Leigh Syndrome patients.
- Populations of mini-brains with ATP6 mutations were grown.
- The mini-brains were studied to characterize the disease and the calcium defects it causes.
- The mini-brains were used to test an existing drug (Sildenafil) to alleviate the calcium defects and increased mitochondrial membrane potential caused by the disease. The results are promising and have already been confirmed by testing it on five patients in Germany.
Future Work
- Currently, a Phase IIa,b clinical trial is being designed, and soon, our children will be able to join to study the promising effects of Sildenafil.
- Study the optimal delivery of the adenovirus to the mini-brains to study the effectiveness of the gene therapies.
- Use the mini-brains to study a large cohort of existing drugs that can benefit ATP6 Leigh Syndrome patients.
- Collaborate with Dr. Gray, Dr. Ling, and Dr. Minczuk to test the gene therapies they develop.
Want to learn more?
Etilogy and diagnosis
The diagnosis of the syndrome is directed by imaging of the brain, showing a specific topology of lesions in the brainstem and basal ganglia, often in conjunction with leukodystrophy and cerebral
atrophy. Elevated levels of lactate in the cerebrospinal fluid and inthe blood have also been observed. The etiological diagnosis is based on genetic testing. Dozens of mutations are known to cause Leigh syndrome. Most of them are located in the nuclear genome. Only between10 and 30% are mitochondrial mutations, the most common of which are the 8993T> G or 8993T> C mutations in the MT-ATP6 gene. Whether themutation is in the nuclear or mitochondrial genome, disruption of any of the complexes of the respiratory chain leads to a significant decrease in the production of adenosine triphosphate (ATP).
Why is ATP important?
Adenosine triphosphate is an organic substance that provides the energy needed to carry out many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. ATP is found in all known life forms and is often called an energy currency. Its deficiency disrupts a number of metabolic processes in the body and leads to the death of the most energy-intensive cells, such as nerve and muscle ones.
Treatment and prognosis
Leigh syndrome involves a short lifespan, usually three to five years. However, some people manage to significantly outlive this age. Supporting therapy focuses on the specific symptoms of each person. Various vitamins, enzymes and antioxidants are used to slow theprogression of the disease. There is still no cure for this disease, but there is already hope. A team of scientists from UT Southwestern Medical Center began developing gene therapy for the mutation in the MT-ATP6 gene. We need YOUR help to make this research into a reality.