Treatments and Disease Management

It is difficult to discuss treatments for CJD, due to the limited understanding of the mechanism of conversion. It is this event which, above all others in the progression of the disease, would be ideal as a target for therapies. Prion protein will always exist endogenously, and so the potential for conversion to disease state prion protein is always there. On top of that, PRNP in the beta-heavy disease state has moderate resistance to proteases (Lloyd et al. 2013). Even if we could use a protease, what would stop it from eating up all the other proteins in the cell? There would need to be a great deal of specificity. According to the NIH, as of a month ago, there is no tried and true treatment to control or cure CJD.

One of the best hopes researchers have is in Kong et al.’s study, which identified a residue that could be altered to make PRNP more resilient to transformation by prions (Kong et al., 2013). There would need to be some small molecule that was capable of inducing a similar change to the protein. Another option for achieving this end would be some type of gene therapy.

Figure 1. Graphical representation of the creation of prion-resilient mice via mutations to increase thermodynamic stability. [Adapted from Kong et al. 2013]
            Something else to consider about CJD and its treatment is specificity, which was touched on before. Unlike a virus, which we can make a vaccine for or a bacterium, which we can target with anti-biotics, there is no immune response to prions because essentially they are just another protein. In some cases of heritable CJD, there is no infection at all, just a mistake made by endogenous proteins. The simplicity of prions makes them a very hard target to latch onto.

There are some talks of using an immunological approach to target prions could be viable (Wisniewski et al., 2012). The problem with some of these approaches, however, is that it is difficult to make a “vaccine” or some sort of prophylactic against prions because our immune system has inborn mechanisms to attack viruses, foreign nucleic acids, bacteria and the like, but not prions. Although our immune system is fairly good at identifying protein epitopes, the question is what would our bodies do when faced with a protein-only invader?

Figure 2. RNAi mechanism of action. RNAi therapy may be an option for the treatment of CJD, which relies on the translation of the prion protein gene into PRNP for substrates for conversion into prions. [ALS via Google Images]
Another alternative may be RNAi. Because of what Kaski’s haplotype analyses told researchers about people with a predisposition for CJD (higher PRNP concentrations) it may be possible to interfere with transcription of new PRNP, which prions rely on to cause the majority of the disease phenotypes, at least in mice (Korth & Peters, 2006).