Researchers have created brain organoids from cells from patients with a rare disease linked to the DHDDS gene, and identified impairments in lipid metabolism, glycosylation, and mitochondrial function. Treatment with NMN, a form of vitamin B3, has shown promise in models and preliminary reports, and an international trial is now planned.
A very rare disease in children, caused by variants in the DHDDS gene, causes severe neurological damage that resembles childhood Parkinson's in some of its characteristics. Children suffering from it may develop tremors, seizures, coordination and learning difficulties, and sometimes a deterioration in movement and independence. Until recently, many families were told that there was no treatment that could slow the progression of the disease.
Now researchers from the Netherlands and the United States report a promising therapeutic direction, born from a combination of parental initiative, stem cell research and “mini-brain” models — brain organoids grown in the lab from patients’ own cells. The findings were presented at the annual conference of the European Society of Human Genetics.
When parents refused to wait
According to Dr. Irena Moffels, a clinical geneticist at the Wilhelmina Children’s Hospital in Utrecht, two parents of children diagnosed with a condition related to DHDDS approached researchers at the Icahn School of Medicine at Mount Sinai in New York. They were told that the only hope was that someone in the research world would choose to study their children’s rare disease. They didn’t want to wait until the disease progressed.
In the laboratory of Prof. Eva Morave-Kozic, researchers have begun creating brain organoids from patients’ cells. In this method, skin or blood cells are taken, reprogrammed to a pluripotent stem cell-like state, and then directed to develop into nerve cells and supporting cells. The result is not a real “brain,” but a small 3D model of brain tissue, allowing researchers to follow processes that cannot be directly examined in the brains of sick children.
After about four months, the organoids showed clear signs of deterioration. The researchers observed a process in the laboratory that resembled the progression of the disease in the patients themselves.
What goes wrong with brain cells?
The DHDDS gene is involved in the production of dolichol, a small fatty molecule that acts as an “anchor” in the process by which cells add sugars to proteins. This process is essential for building glycans—sugar structures that act as “antennas” that help proteins achieve their correct structure and function.
In the mini-brains created by the researchers, it was found that the level of dolichol was greatly reduced, and that the construction of glycans was impaired. In addition, the researchers identified a broader problem in lipid metabolism: the accumulation of cholesterol in astrocytes, support cells in the brain involved in protecting nerve cells. According to the researchers, this accumulation may impair the function of mitochondria — the power plants of the cell — and reduce energy production. This may explain why the disease progresses over time.
Vitamin B3 as a therapeutic direction
Next, the researchers collaborated with the biotechnology company Perlara to screen approved drugs and vitamin supplements that might affect the disease mechanism. In a yeast model of the disease, they found that NMN, nicotinamide mononucleotide—a natural form of vitamin B3 that is involved in NAD⁺ metabolism—was able to improve the condition in the model. When the researchers also tested it in brain organoids, they saw a significant improvement.
According to Dr. Moffles, after the information about NMN reached the families, some of the patients began taking it even before the trials were completed. The researchers reported that within about a month, some of them had seen improvements in their walking, more energy, less tremors, and more fluid movement. Currently, she says, 12 patients are taking NMN, and the first four are already included in the trial.
However, it is important to emphasize that this is still very preliminary data. NMN is available as a supplement, but this report should not be considered a recommendation to take it without medical supervision. In a rare and severe disease, and especially in children, a well-designed trial is needed to test efficacy, dosages, and safety over time.
From a laboratory experiment to an international experiment
The researchers received funding from CDG UK, which supports families with congenital disorders of glycosylation, to begin an international trial of NMN supplementation in DHDDS patients. The plan is for participants to take NMN for a year and be monitored every three months.
The importance of the research is not only in the specific therapeutic direction. It demonstrates how rare diseases, which in the past attracted little industrial interest, can advance thanks to a combination of rapid genetic diagnosis, parental initiative, stem cell models, and collaboration between academia, non-profits, and biotechnology companies.
Professor Alexander Raymond, the conference chairman, who was not involved in the research, said that this is an example of how rapid advances in genetic diagnostics can lead to new treatment directions for rare diseases. He said that when a disease affects very few people, it is usually difficult to arouse industrial interest, so it is impressive to see a common front of parents, associations and researchers around a potential treatment that is relatively cheap and available.
There is still a long way to go, and the researchers themselves emphasize that a controlled trial is needed before solid therapeutic conclusions can be drawn. But for families dealing with a rare and progressive disease, the mere possibility of slowing the deterioration is important research news.
to the notice of the researchershttps://www.eurekalert.org/news-releases/1131675
Short FAQ:
What are “mini-brains”?
These are brain organoids—tiny models of brain tissue grown in the laboratory from stem cells, making it possible to study disease processes without taking samples from patients' brains.
What is DHDDS disease?
This is a very rare genetic disease that affects the nervous system and can cause tremors, seizures, coordination and learning difficulties, and motor deterioration in childhood.
What is NMN?
NMN, or nicotinamide mononucleotide, is a substance related to vitamin B3 and the metabolism of NAD⁺ in cells. In this study, it was tested as a potential therapeutic target.
Is NMN a proven treatment for disease?
Not yet. This is a promising but preliminary finding. A well-organized clinical trial is needed to test efficacy and safety, and this should not be considered a recommendation for use without medical supervision.
