Creating mini-brains from stem cells reveals a new, promising treatment for a devastating childhood disease

by European Society of Human Genetics

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Variants in the DHDDS gene cause a severe neurodegenerative condition, characterized by tremors, seizures, coordination and learning difficulties, usually manifesting in early childhood. This Parkinson's-like condition is extremely rare, and until recently, parents were told there was nothing that could be done to slow its progression. But now, researchers from the Netherlands and the U.S. who created "mini brain" models from patients' own cells to test new therapies have found not only the mechanism of the disease, but also that a naturally occurring form of vitamin B3 (nicotinamide mononucleotide, or NMN) holds significant promise in slowing disease progression.

Presenting the results to the annual conference of the European Society of Human Genetics today, Dr. Irena Muffels, a clinical genetics resident at the Wilhelmina Children's Hospital, Utrecht, the Netherlands, described how two parents contacted researchers at the Icahn School of Medicine at Mount Sinai, New York, U.S., where she was working at the time in the Morava-Kozicz lab. They had been told that the only hope for their two children, who had been diagnosed with DHDDS-related disease, was to wait for researchers to take an interest in the rare disorder.

"But they didn't want to wait," says Dr. Muffels. "They didn't want their children to become wheelchair dependent and unable to take care of themselves due to their movement problems. So they contacted Professor Eva Morava, for whom I was then working. We started creating mini-brains—tiny blobs of brain tissue grown in the lab from patients' own cells*—thus avoiding the need to take samples directly from the children's brains."

The patient-derived mini-brains allowed the researchers to find the DHDDS disease mechanism as well as why it was progressive. After four months, the mini-brains showed clear signs of deterioration, mirroring what happens in real patients.

Normal DHDDS helps produce dolichol, a small lipid "anchor" that carries sugar. In studying the DHDDS mini-brains, the researchers found that this anchor was severely reduced. Sugar also helps build glycans, a kind of antenna that helps proteins perform their correct functions. In the mini-brains, the researchers could see that there were mistakes in the building of these antennae.

Another problem with defective DHDDS is that reduced dolichol affects lipid metabolism as a whole and can lead to significant cholesterol buildup in astrocytes, brain cells involved in neuroprotection. "This accumulation builds over time, and this is why we think the disease progresses," says Dr. Muffels, "since the accumulation of cholesterol leads to mitochondrial dysfunction, leading in turn to reduced energy production."

The researchers collaborated with the biotech company Perlara to identify potential new therapies by screening FDA-approved drugs and vitamins, and found that NMN was able to rescue a yeast model of DHDDS-related disease. They tested the vitamin in the mini-brains and noticed striking improvements. Since this form of vitamin B3 can be bought without a prescription, people started ordering it online before the experiments were completed.

"Within a month we had noticed that these patients' walking improved and that they were more energetic, less shaky, and their movements became more fluid. It really seemed to slow down progression of the disease," says Dr. Muffels.

NMN has been shown to improve molecular mechanisms in muscle cells of patients with mitochondrial disease, a common and devastating pediatric metabolic disorder, and it is currently being tested clinically in these patients. High doses of the vitamin have also been shown to slow progression in Parkinson's disease patients and reduce symptom burden. Due to the plethora of positive effects that vitamin B3 and NMN can induce at the cellular level, other genetic metabolic disorders that affect energy production in the brain could potentially benefit from the treatment.

"The word about NMN reached more DHDDS patients, and we currently have 12 patients taking it. We are starting an international trial for NMN supplementation in DHDDS-related disease," says Dr. Muffels. "Patients will take NMN for a year and will be evaluated every three months. Although I have now left the U.S., I hope that the Wilhelmina Hospital in Utrecht will be one of the official sites and that I may continue to work with these patients."

"There is still a long way to go, but it was encouraging to see how well the creation of the mini-brains helped us mimic the progression of the disease in patients—we could literally see the brains falling apart under the microscope. We were surprised by how fast and how well NMN has worked, and particularly pleased since it is widely available, cheap, and has no known side effects. In some patients, you couldn't even see that they were affected by DHDDS disease after treatment. Now, the first four patients are enrolled in the trial and we are looking forward to being able to help them and their families further in the future."

Chair of the conference, Professor Alexandre Reymond, who was not involved in the research, said, "This study is a perfect example of how rapid progress in genetic diagnosis can lead to new treatments for rare diseases. Because rare diseases such as DHDDS affect so few people, it is usually very difficult to get industry interested. It is impressive that a united front of parents, charities and academics was able to find this promising therapy that is also cheap and widely available."

Key medical concepts

Nicotinamide MononucleotideNeurodegenerative Diseases

Clinical categories

Clinical geneticsChildren's healthNeurologyPediatricsClinical pharmacology Provided by European Society of Human Genetics Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Robert Egan

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