It was about two years ago that National Institutes of Allergies and Infectious Diseases researcher Dr. Cathryn Haigh at Rocky Mountain Laboratory in Hamilton held aloft a flask containing cerebral organoids, a laboratory produced “mini-brain,” that she and her team of scientists used to demonstrate that a prion disease, in this case sporadic Creutzfeldt-Jakob disease (CJD), could be transmitted to human brain cells and studied in vitro in the laboratory.
CJD is a fatal neurodegenerative brain disease of humans believed to be caused by infectious prion protein. It can arise spontaneously, result from a hereditary mutation within the prion gene, or arise due to infection, for example, from eating contaminated meat products. A notable example of this occurred in the United Kingdom in the mid-1990s following an outbreak of bovine spongiform encephalopathy in cattle. There are no preventive or therapeutic treatments for CJD.
Human cerebral organoids are small balls of human brain cells ranging in size from a poppy seed to a small pea. Their organization, structure, and electrical signaling are similar to brain tissue. Because these cerebral organoids can survive in a controlled environment for months, nervous system diseases, like CJD, can be studied over time. The lack of a completely human CJD model has been a considerable barrier hindering the discovery of potential therapies. Studies in mice have failed to identify treatments that were then effective when tried in patients. By using human cerebral organoid CJD they are getting one step closer to identifying potential treatments for the disease.
Haigh and her team didn’t invent the technique of growing cultured brain tissue. Their contribution was in creating this prion infection model by demonstrating that a prion disease can be transmitted to human brain cells. One part of the process that Haigh appreciates is that you don’t need to start with any human brain cells. You make them. All the participating patient has to contribute is a small sample of skin. These skin cells are then “genetically engineered,” reducing them to stem cells and then stimulating the development of brain cells out of that stem component by administering certain hormones.
In their latest article published in Scientific Reports [Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt-Jakob Disease. Scientific Reports DOI: 10.1038/s41598-021-84689-6 (2021)], authors B. Groveman and NC Ferreira et al, describe the laboratory work which involved testing pentosan polysulfate (PPS) to determine its potential preventive and therapeutic benefits. PPS is a benchmark anti-prion compound in laboratory experiments. Haigh calls it the “gold standard.” It is rarely used clinically because it requires direct administration into the brain. Haigh said that, despite its effectiveness at stopping the disease, it would never be a proper therapy because it has to be delivered by pumping directly into the brain and, while it may extend a patient’s life, PPS has not been shown to improve quality of life.
“We don’t just want to stop the disease,” said Haigh, “we want recovery. We want to help the neurons recover normal functioning.”
By using the anti-prion properties of PPS with the new human organoid CJD model, the researchers were able to assess the value of this model system for drug discovery. According to Haigh, the tests showed that the human organoid model can be used to screen compounds that may be useful for preventive treatment.
According to Haigh, two different methods were used in the study. In the first, the brain organoids were infected but at the same time given the PPS treatment to see if it would work as a prophylactic. The second method involved testing the treatment after the infection had fully set in to see if the treatment had therapeutic value.
“Both paradigms showed a really significant reduction in infection,” said Haigh.
Such treatment could be used for people carrying genetic mutations that cause the disease, but who have not yet developed symptoms, or for people who may have been exposed to infectious prion proteins that might cause CJD. The model further proved useful for screening drugs against established CJD after a patient is diagnosed and starts showing symptoms of disease.
Haigh said scientists around the world are working to expand the organoid model for screening larger numbers of novel drug candidates. Their goal is to find treatment options for people who are susceptible to CJD because of their genetics or who accidentally are exposed, as well as for those who develop sporadic disease. They are optimistic that with their fully human model of disease, they can now identify compounds with promise for benefitting patients with CJD.
Cerebral organoids are also being used as models to study Zika virus infection, Alzheimer’s disease, and Down syndrome.
According to Haigh, finding a treatment that can cross the blood/brain barrier and diffuse into the brain without having to be pumped directly into the brain is critical to developing a successful therapeutic treatment for the disease.
“There is so much going on and each little step takes us closer to the summit,” said Haigh.