Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
We previously published about this research in a story titled “Scientists Create First Human Model of Leigh Syndrome,” which can be found here. The study was originally published in the research journal Nature Communications. You can view the full study here.
The team of researchers in this study were affiliated with the University Hospital Duesseldorf, Germany and Berlin Institute for Medical Systems Biology (BIMSB) of the Max Delbrueck Center for Molecular Medicine (MDC).
Leigh syndrome is a severe form of mitochondrial disease that impacts children. As it stands, there is no real treatment or cure for the disease and the majority of patients will die early in life. Efforts to better understand this deadly illness have been hampered so far because of the failure to develop an effective disease model for research. Prior efforts have focused on animal models based on SURF1 gene mutations (which are often found in patients), but these efforts failed to reproduce the clinical characteristics seen in human patients.
In this study, the scientists were able to successfully create a human model of Leigh syndrome instead. The model was developed using CRISPR/Cas9 technology. The team first converted skin cells into stem cells that are able to create neurons. Then the researchers took cells from donor patients and used CRISPR to take the SURF1 mutation from their cells and introduce them to the stem cells. With these mutated stem cells, they also created neurons and brain organoids.
From these first-ever human models of Leigh syndrome, the scientists were immediately able to make some ground-breaking discoveries. The scientists noted that the morphogenesis of the neurons was compromised in the mutated cells, specifically due to a problem with the neural progenitor cells. This problem was an energy deficiency. Ultimately, this can lead to issues with the function of the brain as it develops. This finding was a major step in understanding the mechanism of this rare mitochondrial disease.
Now with an understanding of this mechanism, the team sought a way to intervene and correct the energy deficiency. They opted for augmentation of the SURF1 gene (gene replacement) and also found success in the model with a drug called bezafibrate, which is already approved for use in children. The scientists were able to successfully create both a disease model and find a potential approach that could help with the treatment of this deadly illness.
About Leigh Syndrome
Leigh syndrome is a type of neurometabolic disease that impacts the central nervous system. Levels of thiamine triphosphate or often abnormally low or absent altogether. Mutations of the mitochondrial and nuclear DNA have been implicated in Leigh syndrome, and there are a number of different variants that have been linked to different genetic abnormalities. Symptoms often appear after a triggering event like surgery or an infection which places strain on the child’s body. Symptoms include vomiting, diarrhea, difficulty swallowing, muscle weakness, dystonia, and ataxia. Treatment is mostly supportive, but may include succinic acid, thiamine, or sodium citrate. A high fat low carb diet can benefit patients with X linked Leigh syndrome. Few patients survive beyond their teen years; respiratory failure is the most common cause of death. To learn more about Leigh syndrome, click here.
Why Does it Matter?
Leigh syndrome is a prime example of a rare disease community that is in dire, dire need of progress. Currently patients stand little chance of surviving to adulthood or leading fulfilling life. This is due to lack of research and disease modifying treatments. The achievements from this study stand to change all of that and help make much needed steps forward in the treatment of this devastating illness.
With the creation of a model, researchers across the globe now have real chance at studying Leigh syndrome that is linked to SURF1 genetic mutations effectively and learning how the disease mechanism works. This team has also made great strides in discovered a potential method of intervening in the mechanism and finding potential approaches that could one day lead to a disease modifying therapy.
While more in-depth studies of these strategies, such as treatment with bezafibrate, will be necessary before more concrete steps such as clinical trials can begin, the findings from this study nevertheless herald some meaningful progress for people living with Leigh syndrome.