Prion Disease: Promising Progress in the Journey to a Potential Treatment

What is prion disease?

Prion disease is a devastating, rapidly progressing neurodegenerative disorder caused by the misfolding of the normal cellular prion protein. Misfolded prion is acutely toxic to neurons and its accumulation can result in a range of cognitive, psychiatric and motor deficits. These can include dementia, difficulty walking and changes in gait, hallucinations, muscle stiffness, confusion, fatigue, difficulty speaking and ultimately death.

Currently, there is no known cure and no approved or clinical-stage disease-modifying therapy for the prevention or treatment of prion disease.  This unmet challenge has catalyzed research efforts to better understand the disease.  The need to develop novel therapeutics is urgent, as prion disease affects people all over the world, including over five hundred newly diagnosed cases each year in the US, with thousands more estimated to be at risk for an inherited form of the disease.  

A potential solution: epigenetic regulation

What if we could interrupt, or even turn off, the spread of misfolded, toxic prion proteins? That’s the idea behind epigenetic regulation, the process by which the expression of a particular gene is controlled – either by dialing it up or, in this case, dialing it down. By reducing the expression of prion proteins in brain cells, we attempt to reduce accumulation of misfolded prion proteins, limit damage to neurons, and therefore alleviate progression of the disease. Accomplishing this goal means making incredibly precise and specific epigenetic changes to alter the expression of the prion gene without impacting other genes in the cell. That’s the kind of precision that zinc finger technology has been designed and developed to achieve.

Zinc fingers are human-derived proteins which naturally regulate the genome through sequence-specific interactions with DNA and regulatory proteins. At Sangamo, we aim to engineer zinc finger proteins to therapeutically lower or eliminate protein expression, thereby targeting the root cause of prion disease and many other similarly challenging diseases caused by toxic misfolded proteins. We design zinc finger transcriptional regulators to recognize and bind to a specific DNA sequence within a particular gene, potentially allowing expression of that target gene to be precisely controlled.

Think of a gene as an instrument in an orchestra: all the instruments need to be in harmony to make the best music.  If one instrument is too loud or too quiet, it will disrupt the balance of the symphony. Our zinc finger technology enables us to selectively adjust the volume of the disruptive instrument without impacting the rest of the orchestra.

For prion disease, we are using zinc finger repressors (ZF-Rs) to “turn down” the activity of the prion gene and its protein product with the ultimate goal of delaying, stopping and even reversing disease.

Seeing ZF-Rs in action against prion disease

In our preclinical research in cellular and animal models, we have observed the effects of these powerful gene regulators.  In the presence of the accumulation of misfolded prion proteins, preclinical treatment with our ZF-Rs significantly decreased the levels of prion gene expression by 40-70% throughout the brain and the cerebrospinal fluid. In the lab environment, when we use ZF-Rs to treat prion-infected brains, we saw a remarkable reduction in toxicity.  Treatment in a preclinical setting dramatically extended survival, improved weight gain, and delayed a rise in plasma levels of neurofilament light chain protein, an established biomarker of neurodegenerative disease progression. As we work to continue development of our program and hopefully advance into human trials, we will evaluate whether this type of outcome continues to hold true in a clinical setting.

We presented our latest preclinical data for a potential prion disease therapy at the 2023 American Society for Gene and Cell Therapy (ASGCT) annual meeting in Los Angeles, CA in May this year and in October at the International Prion 2023 conference in Portugal. The data presented from these studies revealed interesting and promising preclinical results that are helping us develop what we hope will one day become an effective therapeutic. Click on the applicable links below to view the materials presented at these conferences:

• ASGCT
• Prion Conference

Potential to change the treatment landscape

These promising results support our ongoing preclinical research efforts. While a potential cure is not imminent, we are hopeful about these results and our efforts to help change the story for patients with this devastating, unmet medical need.

Authored by Sangamo Therapeutics