Nanalyze

When Will There Be a Cure for Creutzfeldt-Jakob Disease?

It all started last December when Shany, a 59-year-old Canadian woman, suddenly lost her ability to write, text, drive. She also started hallucinating and her memory was malfunctioning. She couldn’t remember her computer password, something she always knew. For some unknown reason her mind couldn’t seem to connect with her hands. A few days later, her son took her to the emergency room where doctors speculated that the cause could be the early onset of dementia. Her symptoms became progressively worse, and a few weeks later she was admitted to the hospital where they thought she might be having a stroke. Only after a CT scan, MRI, and a spinal tap, did they reach the conclusion that Shany had contracted Creutzfeldt-Jakob Disease (CJD).

Another week passed, and Shany was quickly losing all speech, couldn’t walk without assistance, had only sporadic memories, and her hallucinations became much worse. With nothing they could do for her, doctors sent her home to die. After 10 more days, she lost all her functions, her organs shut down, and she died. Shany was loved dearly by her friends and family who could only ask one question. Why Shany?

What is Creutzfeldt-Jakob Disease?

Creutzfeldt-Jakob Disease or CJD is a “rare, degenerative, fatal brain disorder” that affects about 1 in a million people – so about 350 cases in the United States per year. It belongs to a group of diseases called “prion diseases” and is the most common one. (For example, “mad cow disease” is a prion disease that affects cows.) While CJD may be extremely rare, in 85% of cases it occurs sporadically with no known cause (the other 15% of cases can be tied to a genetic predisposition). You may have heard of CJD being associated with mad cow disease because they’re both prion diseases that leave brain tissue perforated with holes over time. While there is a variant of the disease that can be acquired by eating meat from cattle that are infected with mad cow disease, cases of acquired CJD are less than 1% of the overall number.

CJD divided into multiple forms

Source: The Netherlands Journal of Medicine

While the cause of CJD is not entirely understood yet, the problem occurs with something called a “prion protein.” The PRNP gene provides instructions for making a protein called a “prion protein” or PrP which is most often expressed in the nervous system. CJD occurs when this protein starts misfolding and causing other prion proteins around it to misfold. The misfolded proteins – called prions – then form structures called amyloid plaques which create the aforementioned holes in the brain tissue. While it’s not known what causes the proteins to suddenly start misfolding, once the process starts, it becomes a chain reaction that can’t be stopped.

A Cure for Creutzfeldt-Jakob Disease

There is no present cure for CJD, and treatment involves making the patient as comfortable as possible as they quickly move towards death. (It usually happens around the age of 60 and 90% of people will die within a year.) Since we don’t know what causes CJD, it’s awful hard to know how we can prevent it from occurring. Scientists have been able to take stem cells and infect them with the disease, which is a start towards better understanding it. In other recent news, scientists were able to create the first synthetic prion which can help them identify potential therapies. There’s a good reason behind this need for creativity. Because of the nature of this disease, it’s been particularly difficult to run clinical studies on potential treatments.

The challenges associated with developing a treatment surround how CJD is incompatible with the traditional method of approving drugs through clinical trials. The first problem that needs solving is the ability to accurately diagnose the disease the first time around. One study with 97 patients found that only 18% were diagnosed correctly at their first assessment. The mean time from onset to diagnosis was 7.9 months, meaning the disease had already progressed two-thirds of the way when it was finally found.

On average, a patient is misdiagnosed 4X before they finally receive the correct diagnosis. One promising study a few years back found that using deep learning, researchers were “able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from Rapidly Progressing Dementia (RPD).” Progress in this area happens quickly. Scientists can now use machine learning to detect Alzheimer’s disease in brain scans six years before a diagnosis.

Then, there’s the matter of patient ability and willingness to participate in studies. Because the disease progresses so quickly and isn’t properly diagnosed in early stages, it’s difficult to find patients in earlier stages where potential treatments might prove more effective. When it comes to patient willingness, as one study noted, there was a “refusal to give informed consent due to the risk of receiving a placebo for a fatal disease” indicating the patients much rather prefer just being given any new treatment so they can have some degree of hope. That’s what has been happening in the U.K. recently.

The PRN100 Antibody

Given the challenges associated with treating the disease, it seems logical that we should bend the rules a bit and let patients take on more risk trying experimental treatments since they have nothing to lose. That was recently the case in the United Kingdom where researchers have now treated at least four patients with the PRN100 drug which was developed by researchers at the Medical Research Council (MRC) Prion Unit at University College London (UCL). They have several potential treatment options in the pipeline including agents that target the healthy form of the prion protein (PrP). The approach being taken is described as follows:

There is substantial evidence for effectiveness and safety of antibody treatments which bind to PrP. Antibodies are proteins found in the blood and made by immune cells. They are used by our immune system to help fight infections. As PrP is one of the body’s own proteins we do not naturally make antibodies against prions. However, we have been able to make antibodies in mice and then, by genetic engineering, make human versions of these antibodies. Antibodies that bind to PrP can cure prion-infected nerve cells growing in the laboratory. We think that the treatment works by removing the normal form of PrP required for prions to grow.

They go on to talk about how PRN100 is a human antibody manufactured from the mouse antibody ICSM18. PRN100 binds extremely tightly to PrP. In prion-infected mice, PRN100 can extend survival time from less than 200 days to a normal lifespan (> 600 days), with these long surviving mice showing no evidence of prion infection when their organs are examined after death. Essentially, these mice are cured. The last update we can see is that four patients have now been treated and it’s too early to say if the treatment is working. We emailed them with some obvious questions and will update when we hear back.

Update 3/14/2019 – We received a response from UCL stating that the most up-to-date statement they have on PRN100 is the one we have have referenced above.

An Antisense Oligonucleotide

One homegrown effort we came across that’s worth noting is the work being done by two PhD students in biology at Harvard Medical School who decided to dedicate a good chunk of their lives trying to fight CJD. One of them, Sonia Vallabh, learned that she was genetically predisposed to CJD when her mother died from the disease. A genetic test confirmed that the odds of her contracting the disease moved from one in a million to one in two. Sonia and her partner established a non-profit and are now dedicating their lives to developing therapies for prion diseases like CJD. They’re now working with Ionis Pharmaceuticals (IONS) to develop an antisense oligonucleotide (ASO) that could be used to treat CJD.

The premise behind the ASO therapy is simple. Get rid of the prion proteins and the disease can’t occur in the first place. Or, you can get rid of some prion proteins which will slow the progression of the disease. When you have two people knocking on the door of a pharmaceutical company asking for help, you know there aren’t many irons in the fire. Political commentary site Wired published an article about their story titled One Couple’s Tireless Crusade to Stop a Genetic Killer if you’re interested in learning more about their heartwarming story.

Conclusion

We did a fair number of Google searches for companies working on therapeutics for CJD and just didn’t find a whole lot going on other than what we’ve mentioned so far. If you know of some, please drop us a note in the comments section (nothing about Dr. Ufa in Nigeria please). Common sense tells us that rare diseases will receive very little attention when it comes to time spent by researchers and pharmaceutical companies searching for a cure. It’s a little something we refer to as “opportunity cost.”

However, the scientific community now has an incredibly useful toolbox called genetic engineering which allows us to create new and novel treatments much more easily. As a society, perhaps we ought to give researchers more leeway when it comes to allowing consenting adults to receive experimental treatments since they have literally nothing to lose.

We think this AI-powered weight loss app could be a multi-billion dollar business - not because it's backed by the world's most sophisticated investors - but because it works. If you want to lose weight and keep it off for good, check out Noom. People who use Noom lose weight and keep it off for good.

Don’t have your M.D.?

We can help. Our MBAs will keep you informed about life sciences.