Science with Sandra – Publications from Columbia University
Hello and welcome to Science with Sandra!
For this edition, I would like to highlight two studies by Dr. Umrao Monani, Dr. Maoxue Tang, and their teams. Dr. Monani is a Professor of Pediatric Neurology at Columbia University, and Dr. Tang is an Assistant Professor of Neurological Science (in Neurology) also at Columbia University. Both of these wonderful scientists are part of our research community and one of their areas of focus is to have a better understanding of GLUT1 Deficiency and to develop better treatments for this condition.
The title of the first publication, in pre-print and currently in the review process, is “A transgene harboring the human Glucose Transporter 1 (GLUT1) gene locus ameliorates disease in GLUT1 deficiency syndrome model mice”.
What is the study about?
The current standard of treatment for GLUT1 Deficiency is the ketogenic dietary therapy, which gives the brain ketones as an alternative energy source. While this therapy helps many patients, especially for seizure control, it doesn’t fully address the brain’s glucose shortage and in many patients, it does not help to improve movement problems or developmental delays. Additionally, not all patients respond to the ketogenic dietary therapy.
Dr. Monani and Dr. Tang point out that one of the limitations of the current treatment is that although it supplies the brain with ketones, an alternate energy source, it does not address the underlying cause, low brain GLUT1 and deficient cerebral glucose. They state that one straightforward solution to this would be to restore GLUT1 levels to the GLUT1 deficient brain.
What did the researchers do?
The researchers used an existing GLUT1 Deficiency mouse model and inserted a genomic fragment of the human SLC2A1 gene, which encodes the human GLUT1 protein.
The purpose was to correct the underlying cause of GLUT1 Deficiency: low levels of the GLUT1 protein in the brain. They did this by creating genetically modified mice with a human version of the SLC2A1 gene, which encodes the GLUT1 protein, by inserting it into the mice DNA. This transgene included:
- The full human SLC2A1 gene with all its regulatory elements
- A special non-coding RNA (lncRNA), which may help regulate GLUT1 expression
They bred these mice with a haploinsufficiency mouse model of GLUT1 Deficiency, which carries only one working copy of the SLC2A1 gene.
What Were the Results?
Mice with the human SLC2A1 gene showed several improvements compared to untreated GLUT1-deficient mice:
- More GLUT1 in the Brain
- Brain tissue showed increased GLUT1 protein levels.
- This included both human GLUT1 protein and an increase in the mouse’s own Glut1 protein.
2. Better Glucose Levels
- Glucose levels in the cerebrospinal fluid (CSF) were significantly higher.
- Some mice also had slightly higher blood glucose, which may have helped increase glucose in the brain.
3. Improved Brain Function
- Mice improved motor control.
- EEG recordings showed fewer seizure-like brain wave patterns.
4. Normalized Lactate Levels
- CSF lactate returned to normal in treated mice.
In addition of the importance of the study in the gene therapy field, the development of this new model of GLUT1 Deficiency is important because it could potentially be used to test new therapeutical agents that aim to alter human GLUT1 protein.
The title of the second publication I would like to highlight, also in pre-print, is: “A therapeutic role for a regulatory glucose transporter 1 (Glut1)-associated natural antisense transcript”.
What did the researchers do?
Dr. Tang, Dr. Monani and their teams found a special type of RNA called a long non-coding RNA (lncRNA), which they named SLC2A1-DT and was found to be involved in the regulation of the SLC2A1 gene and was used in the above publication.
The researchers used different human cells including brain endothelial cells and introduced SLC2A1-DT into the humanized Glut1 deficient mice publication described above.
What did the researchers find?
Researchers found that:
- Increasing the levels of SLC2A1-DT led to more GLUT1 protein, while lowering the levels of SLC2A1-DT led to lower levels of the protein.
- Mice containing SLC2A1-DT showed improved motor performance, as well as improved CSF glucose levels, CSF: blood glucose ratios and CSF lactate levels.
- Mice showed a reduction in seizures and less brain inflammation.
- Additionally, researchers found that the lncRNA regulates SLC2A1 across species.
These findings led the researchers to inquire if delivering SLC2A1-DT to Glut1 deficient mice would be a viable possibility for treatment. The research team used a gene therapy vector to deliver SLC2A1-DT and found:
- Treated mice showed reduced seizures
- Improved CSF glucose and CSF: blood glucose levels
- Reduced brain inflammation
Study highlights:
- lncRNA is involved in SLC2A1 gene regulation
- Delivering lncRNA to Glut1 Deficiency mice via viral vectors induce Glut1 expression increasing brain glucose levels
- This new treatment approach could not only be used to treat GLUT1 deficiency but other conditions where GLUT1 is low such as Alzheimer’s disease.
We thank Dr. Monani, Dr. Tang and their teams for their work and for their interest to support our community.
If you have any questions, please feel free to reach out to me at [email protected].Thank you for visiting our blog!
