Last week at the annual conference of the European Society of Human Genetics in Gothenburg, Sweden, researchers presented work on the first cortical brain organoid models of dehydrodolichyl diphosphate synthase (DHDSS)-related disease — a condition with no current treatments. The pioneering work, led by Eva Morava and Tamas Kozicz's team at the Icahn School of Medicine at Mount Sinai, allowed the scientists to not only elucidate the mechanism of the disease, but also test out a widely available therapeutic — nicotinamide mononucleotide (NMN), better known as vitamin B3.
Morava is a metabolic geneticist who focuses on the diagnosis and treatment of congenital disorders of glycosylation (CDG), where her clinic sees patients from all over the world. DHDSS-related disease is one genetic type of CDG that causes neurodegeneration that leads to tremors, seizures, and cognitive and developmental delays. To develop the brain organoids without taking an invasive sample from the brain, her team used patient skin biopsy fibroblasts reprogrammed into stem cells, and then into neurons.
“We are the first research team who developed cortical brain organoids in the disease group CDG,” Morava told DDN. “Having this model available for a patient with rare disease allows us to develop personalized treatments for the genetic disorder representing the exact and full genetic makeup in disease-relevant tissue.”
Finding the mechanisms of disease
The work started after two parents of a child with DHDSS-related disease reached out to Morava, explained Irena Muffels, who was a postdoctoral researcher in the Morava Kozicz lab during the work, in the press release. “They didn’t want their children to become wheelchair-dependent and unable to take care of themselves due to their movement problems,” Muffels said.
Morava’s team quickly got to work. They created the cortical organoids or “mini brains” from skin biopsies of patients and healthy controls that they had reprogrammed into embryonic stem cells, and then back to neuronal cells. The researchers tested metabolic activity, brain structure, cell types, fat storage, and electrical activity.
After just four months of culturing, the researchers found that the DHDDS-patient derived organoids were showing obvious visual signs of degeneration. Revealing the mechanisms leading to progression of disease, they also showed substantial accumulation of cholesterol in astrocytes, fewer deep layer neurons, and depletion of dolichol, a lipid that carries sugar. Using proteomic analysis, they also demonstrated altered expression of proteins involved in lipid metabolism, cytoskeletal organization, and neuronal development.
Identifying a treatment
In collaboration with Perlara, the scientists then went looking for therapies that could treat these impairments in lipid metabolism, glycosylation, and mitochondrial dysfunction. In a yeast model, they found that NMN could treat the disease, and could also reverse the disease in the human brain organoids.
“Based on our data we approved the patient’s initiative to trial NMN as N-of-1 trials in several patients who were in the natural history for CDG with the safe [over-the-counter] supplement NMN,” said Morava.
The patients who started taking NMN quickly showed improvements in their walking that the researchers could quantify using AI to analyze their home videos. The results align with the known benefits of NMN in patients with mitochondrial disease, as NMN inhibits mTOR (mechanstic target of rapamycin) signaling and PPAR (perozisome proliferator-activated receptor) activation that then leads to the biogenesis of mitochondria.
Morava and Kozicz's lab has now started a Phase 1 clinical trial to test NMN in more patients with DHDSS-related disease.
“There is so much more to do!” said Morava. Her team plans to continue investigation of the patient derived brain organoids to discover what leads to the abnormal lipid metabolism and develop new treatments.
Morava also noted plans to collaborate with other researchers to develop diagnostic biomarkers and evaluate other treatments — and hopefully soon get to direct genetic therapies as well.
