There is currently no therapy for Creutzfeldt-Jakob disease (CJD), in which misfolded proteins destroy the brain. Researchers have now developed a monoclonal antibody that is intended to limit damage to the brain. As part of an exemption, they tested this therapy on six CJD patients – with promising results. Although all patients succumbed to their disease, the antibodies reached the brain beforehand and may have slowed the worsening of symptoms in three test subjects. In addition, there were no side effects. Clinical studies with more patients are now to follow.
In Creutzfeldt-Jakob disease (CJD), misfolded proteins called prions form in the brain. These attach themselves to other proteins, so that these are also misfolded and the disease spreads in the brain. Brain scans of those affected show that the brain decomposes like a spongy – similar to cattle suffering from bovine spongiform encephalopathy (BSE), which is also caused by prions. Symptoms include rapidly progressing dementia, uncontrollable muscle movements and mental health problems.
The disease can be transmitted, among other things, by eating beef contaminated with BSE pathogens and by blood transfusions or transplants from a donor who had undetected CJD. In familial CJD, mutations in the genome increase the risk of misfolded proteins. In addition, in rare cases, the disease occurs spontaneously without an identifiable cause, especially in people over 60 years of age. There is no therapy so far. Most sufferers die within a few months of diagnosis.
Antibodies against prions
A team led by Simon Mead from University College London has now developed a possible treatment approach and tested it on six patients. To do this, the researchers developed a monoclonal antibody called PRN100, which is able to bind to the very proteins in the brain that misfold to form the diseased prions. Previous studies in cell cultures and mice had shown that the antibody can protect healthy proteins from also misfolding. In this way, the researchers hope, the spread of the disease in the brain could be contained.
“Between October 2018 and July 2019, we treated six patients, two males and four females, with PRN100,” Mead and his colleagues report. Since this was the first human trial, they increased the dose slowly and monitored closely for side effects. Starting with one milligram per kilogram of body weight, the researchers gradually increased the dose up to 120 milligrams per kilogram of body weight. “Our cautious dose escalation meant that it took a very long time to reach the target concentration of the drug in CSF,” the researchers explain. Two patients died from their disease before the target concentration was reached, one after seven days and one after 30 days. The other patients were treated for between 50 and 260 days before succumbing to their disease. None of them experienced any side effects.
Symptoms stabilized
In each patient, Mead and his colleagues regularly assessed how far the disease had progressed. To do this, they used the so-called Prion Disease Rating Scale, a standardized examination method to record motor and cognitive abilities. They compared the results with historical controls: For an earlier study on the course of Creutzfeldt-Jakob disease, the same tests were carried out with untreated patients between 2008 and 2018. Mead and his team selected patients who were similar to those treated in terms of age, gender, disease stage and other characteristics as comparison persons.
“Although disease progression was not halted or reversed in any patient, values on the Prion Disease Rating Scale appeared to stabilize in three patients during periods when CSF drug concentrations reached target concentrations,” the researchers report. However, due to the small number of subjects, statistical analyzes were not possible in a meaningful way. Furthermore, the drug was not administered as part of a clinical trial, but rather under an exemption permitting the use of an unapproved drug in patients for whom no other treatment option is available.
Basis for clinical studies
“We still have a long way to go, but we’ve learned a lot, and these results now justify conducting a formal clinical trial with a larger number of patients,” says Mead’s colleague John Collinge. He hopes that the drug will actually help against the disease and can possibly also be used preventively in people who have a high risk of disease due to genetic mutations or contact with prions. The research could also be relevant for other neurodegenerative diseases that also involve misfolded proteins in the brain, including Alzheimer’s disease.
Source: Simon Mead (University College London, UK) et al., Lancet Neurology, doi: 10.1016/PIIS1474-4422