New trial hopes to use mRNA to halt the devastating progression of CJD

Prion diseases came to public attention during the 1980s and '90s, when Mad Cow Disease was in the news. While transmission to humans from infected beef has largely been eliminated, other forms of these devastating diseases are unfortunately still around, like Creutzfeld-Jacob Disease (CJD). In fact, according to the US Centers for Disease Control, cases of CJD have been on the rise in the last two decades.

The Alzheimer Society of Canada describes CJD as a rare and fatal form of dementia, caused by the formation of aggregates of a protein, called prion protein, which are highly toxic for the brain. Early symptoms can be mild, like depression, mood swings or confusion. Once symptoms start, they progress very quickly. Eventually, the person loses the ability to move, speak or care for themselves.

Fast progression

"This is really a dreadful disease, and it has a particularly extreme severity. Last year, I diagnosed a man whose first symptom was confusion playing cards—he couldn't remember the rules. He was diagnosed at the end of January and died in early March," said Dr. Massimo Pandolfo, co-director of the Clinical Research Unit at The Neuro (CRU) and a principal investigator on a new clinical trial for CJD at The Neuro.

Most CJD cases happen because some aggregates of prion protein spontaneously form in the brain and are not quickly eliminated (sporadic CJD). Some individuals inherit a variant of the gene encoding a form of prion protein that is highly prone to aggregate (familial forms). In all cases, abnormal aggregates of the prion protein rapidly expand by recruiting the normal protein present in the brain, causing a chain reaction.

On average, the familial forms occur at a younger age, between 20 to 40 years of age. However, according to the Alzheimer Association, the vast majority (85%) of cases are sporadic.

RNA to the rescue?

"There is no treatment to slow progression. Once individuals become symptomatic with typical CJD, the median survival is less than six months," confirms Dr. Pandolfo. A new study at the CRU hopes to lead to a very different outcome for these patients.

The study underway at The Neuro is the first ever in Canada to evaluate whether a treatment using an antisense oligonucleotide (ASO) therapy would be effective at stopping the misfolding of the prion protein, stalling the progression of the disease. ASOs are short strings of nucleotides—the chemical building blocks of our genetic code—that are designed to attach to a specific sequence of messenger RNA. Similar to gene therapy, they allow researchers to precisely target the therapy to a defective gene.

"One of the things you can do with ASO is repress the expression of a gene. If your body stops expressing the prion protein, we should be able to slow or stop the process," explains Dr. Pandolfo. ASO therapy has already been used successfully to treat other neurological conditions, and data in animal models that confirm that lowering the expression of prion protein significantly delay and slow CJD.

"While the disease is rare, it leaves patients very little time with loved ones. We hope that some individuals will choose to help advance treatments by participating in research like this study," concludes Dr. Pandolfo.

Provided by McGill University