The development of therapeutics for transmissible spongiform encephalopathies (TSEs) continues to be challenged by the complex nature of these diseases. Also referred to as prion diseases, TSEs are rare and fatal neurodegenerative conditions.
As per the prevailing prion theory, a misfolded version of a normal cell-surface protein acts as the chief infectious agent. While other mechanisms of disease involving canonical, virus-like infectious agents have been long proposed, investigational therapies in this space, which are few and far between, have mostly focused on targeting the prion protein (PrP) so far.
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By GlobalDataTSEs include Creutzfeldt-Jakob disease (CJD), and Kuru or Gerstmann-Sträussler-Scheinker syndrome. CJD is the most common, with roughly 350 cases being reported in the US every year. Variant CJD (vCJD), a disease linked to the consumption of beef infected with bovine spongiform encephalopathy (also known as “mad cow disease”), previously made headlines when an outbreak was reported in the UK during the 1990s.
The rareness of prion diseases makes the prospects of a return on investment for companies difficult. “That is of course a problem with all rare diseases, but this [CJD] is not even rare. It is ultra-rare,” says Jesús Rodriguez Requena, PhD, associate professor in the Department of Medicine at the University of Santiago de Compostela. As per the National Institute of Neurological Disorders and Stroke, about one individual in a million is affected by CJD globally.
The rareness of these indications also means that treatments will likely not be profitable, even if priced highly, says Requena. This is also why academic research is dominant here, as companies are hesitant to take this on, adds Holger Wille, PhD, associate professor at the Centre for Prions and Protein Folding Diseases at the University of Alberta.
However, delivering a functioning treatment could have a prestigious, symbolic value, says Requena. In addition, the lethality of prion diseases effectively means that any effective treatment could be fast-tracked into the clinic, streamlining the regulatory journey for companies, says Wille.
No progress in drug discovery
“We have made astonishing progress in understanding the disease….On the other hand, I think the progress in drug discovery is nil,” comments Requena on the prion disease landscape. “Unfortunately, right now, a patient diagnosed with the disease has absolutely no hope of getting any treatment.”
According to GlobalData’s Pharma Intelligence Center, there are only six drugs in active development for CJD, of which only one has been in clinical trials. This list includes the monoclonal antibody (mAb) PRN100 developed at University College London (UCL) and ALX-002, a treatment developed by Allyx Therapeutics that is also being studied for Alzheimer’s disease. GlobalData is the parent company of Pharmaceutical Technology.
Although there were efforts to develop or repurpose certain treatments, they were unsuccessful, says Wille. This includes the antiprotozoal drug quinacrine, also known as mepacrine, which was seen as promising but ultimately did not perform in the clinic, explains Wille. Requena names the antibiotic doxycycline as a further example of a drug that performed well in cell and animal models, but not in humans.
A significant obstacle in the development of therapeutics is how the diseases themselves manifest. According to Wille, 90% of prion diseases in humans are sporadic. This means that their cause is unknown and, by the time a patient is diagnosed, the disease has progressed to an advanced stage with considerable damage already done, Wille says.
With sporadic diseases, the main clue is in the patient's age, as sporadic CJD is an age-related disease, Wille says. But 10% of the cases are caused by genetic factors, meaning patients inherit the condition through familial links. Here, one could monitor the situation closely and look for those with a likelihood of being a carrier, he says.
Adding to this, the infectivity of prion diseases also makes research challenging, says Wille. Since research needs to be done under containment conditions, samples cannot be moved across different facilities, he explains. For example, in his own experience, Wille found it difficult to do single-cell sequencing or other expensive procedures, because those tools were not within a designated containment area.
Qingzhong Kong, PhD, associate professor at the Case Western Reserve University’s School of Medicine, says that the first challenge in bringing any potential treatment to the clinic is in finding enough patients. But even when a study has patients, their life expectancy is very short, Kong says.
And then comes the question of the right target. “There is an enormous emphasis on prion protein and prion protein folding,” says Dr. Laura Manuelidis, professor of neuropathology at the Yale School of Medicine. “If one doesn't know what the infectious agent really is, how can you possibly attack it,” she adds. Her view is that while prion protein misfolding may be part of host response, we know little about the sophisticated immunology involving host responses to the infectious agent.
On the subject of targeting PrP, if you remove it from an organism, then the disease cannot progress, so it's absolutely a requirement, says Wille. While virus-like agents could play a role as a risk factor for spontaneous prion disease, the times of debating their role of as the cause of these diseases have passed, says Byron Caughey, PhD, Chief of the TSE/Prion Biochemistry Section at the National Institute of Allergy and Infectious Diseases (NIAID). Wille does not see a viable alternative mechanism that could be targeted by drugs apart from those already studied. That said, if one appears, it should be rigorously examined, he adds.
Another approach taken by University of Edinburgh professor and Personal Chair of Immunopathology Neil Mabbott, PhD, is to look at how prion protein gets from the gut into the brain. So, while abnormal prion proteins are a mark of the disease, his work investigates how prion proteins hijack intestinal M cells and spread further, Mabbott says. This means that the removal of M cells could prevent the accumulation of prion proteins in the body. In this sense, understanding how prions hijack the M cells could lead to the identification of future treatments, he adds.
Reaching a consensus on the etiopathogenesis of disease is particularly relevant now given the recent controversy for another neurodegenerative condition—Alzheimer’s disease. Allegations of image manipulation in research papers supporting the amyloid theory have emerged, which cast a shadow on several drugs that were designed with that target in mind. That said, Requena adds that there are other studies, which still make the amyloid theory relevant.
There has not been much success in halting Alzheimer’s or Parkinson’s that have a much longer duration than the rapid progression of TSEs, which makes it more difficult to research a treatment, says Wille.
Manuelidis contends the prion protein focus has taken up millions of dollars in research, just as billions of dollars have been spent on researching amyloid beta. There has to be an understanding that we don't know everything about this infection, the infectious agent, and this disease, and there's a lot more to learn, she says.
We still do not know how prions eventually damage and kill neurons, Requena says. To him, being open to other views is the nature of healthy science. “I think it is very healthy that all angles are covered….The very nature of science is that you look at things and from different angles.”
Movement in imaging and exploratory therapeutics
In March 2022, a UCL-based team from the MRC Prion Unit and Institute of Prion Diseases shared findings from a Phase I study that tested a mAb, PRN100, that they developed, in six patients. The mAb was being tested as the first treatment targeting the cellular prion protein (PrPc) in humans.
The treatment did not halt or reverse disease progression in any of the subjects. That said, it was well tolerated, and three patients did present a certain stabilization of clinical rating scale scores for periods of time. The team considers the results preliminary, and they could be used to move into larger studies. Requena says that while the findings are interesting, they are limited by the small number of patients.
According to Mabbott, a challenge with developing mAbs or vaccines is their potential toxicity. There are only a few antibodies that can specifically recognize the (abnormal) version of the prion protein.
Another approach involves the use of antisense oligonucleotides (ASOs) as a therapeutic, which have attractive life-prolonging effects, says Caughey, who is involved in this research. The concept here is to reduce the number of normal prion proteins available for prion replication, which could result in extended survival, he explains.
According to research done by the NIAID, Ionis Pharmaceuticals, and the Broad Institute, one injection of an ASO given to mice 120 days after infection prolonged survival by 87 days. According to a February 2022 company update, Ionis Pharmaceuticals will study ION717 for prion diseases in a Phase I/II in H2 this year. But here, crossing the blood-brain barrier will be a major challenge, says Requena.
Other approaches include the development of a vaccine, an approach explored by Wille, as well as using folding intermediates as a drug target. His team is also looking at ways to link the concept of a prion vaccine to a vaccine for Alzheimer’s and Parkinson’s, he adds. At the same time, a vaccine based purely on prion protein has a good chance of generating neurotoxic antibodies, warns Mabbott. He says that a vaccine could be used for those with familial links and against acquired prion diseases like vCJD. There are other efforts looking at the use of CRISPR/Cas9 as a tool against prion proteins.
Further developments in prion protein imaging could play a key role in discovering new treatment pathways. Caughey, together with researchers from Case Western Reserve University, published findings in Nature Communications that described a new prion structure—a second prion strain, which gives insight into how prions are formed.
Previously, the haphazard nature of prions made their study difficult at higher resolutions through conventional technologies, he explains. But new cryo-EM techniques used in this study gave the field the first real images of what prions are and what shape they take.
“Knowing the structure helps people rationalize the development of potential therapeutics, whether they’re small molecules that prevent prion replication, or vaccines that are trying to elicit antibodies to block prion propagation in the host,” says Caughey. In a sense, knowledge of the structure underpins everything in development, be it better diagnostic tests or treatments, he adds.
