Overall, while valuable insight into human African trypanosomiasis has been gained over time, there is still question as to the exact mechanism by which the trypanosomes cause disease in the central nervous system, as well as how they access the central nervous system in the first place. There is also mystery as to how existing theraputics work, as well as a dearth of treatments that are effective and feasible to use. I have several proposals regarding where research should go next.
1) An attempt to make a variation on eflornithine that has a longer half-life
Eflornithine is the most effective and safest treatment currently available for stage two HAT. As was mentioned on the “Treatment and Disease Management” page, the issue with Eflornithine is that it has an extremely short half-life, necessitating constant administration to patients which is unrealistic in the circumstances in which doctors are treating HAT. If an eflornithine derivative could be developed that had longer half-life, perhaps it could be effective, safe, and plausible to use. Another option is to find a drug to use in conjunction with eflornithine that either helps to extend its half-life via an in-body reaction.
2) Development of a theraputic that binds to hemoglobin and can disable the parasite via the TbHpHb receptor
Perhaps a drug could be developed that binds to hemoglobin in such a way that the complex can bind to the trypanosome’s TbHpHb receptor, and essentially deactivate the trypanosome by blocking the receptor’s surface, starving it of heme. In this sense, the drug would work similarly to TLF/HPR/hemoglobin, but, instead of sending in APOL1 to destroy the trypanosome, it would essentially starve the trypanosome of a necessary cofactor.
3) Focus on theraputics that do not cross the blood-brain-barrier
This is a fairly risky proposal, but many of the ill effects of melarsoprol occur because the drug and the trypanosomes that it kills accumulate in the brain. Mogk et al. hypothesized in the fall of 2014 that it seems more likely that trypanosomes invade the central nervous system via the blood-cerebrospinal fluid barrier. If one could target this barrier instead of the blood-brain barrier, perhaps a drug could be developed that did not have as many adverse side effects. The problem with this proposal is that, as of now, transitioning to the central nervous system via the blood-cerebrospinal fluid barrier is still a hypothesis. To get approval for theraputic development, it would likely have to be proven, which is difficult since there is no animal model for HAT, and infected brain tissue can only be viewed post-mortem, if at all. Still, it would be worth investigating, given the toxicity of melarsoprol and the unrealistic nature of eflornithine administration.
It is also worth mentioning that vector control could be (and has been) effective at preventing trypanosomiasis from spreading. This would focus on the extermination of the tsetse fly.
Another research area that is worth pursuing is the characterization of the VSGs in the trypanosomal genome. If all of their functions were known, then VSGs critical for virulence could be identified. While immunotherapy for VSGs would be inherently difficult due to their variant nature, if all of the VSGs critical for virulence were identified, then perhaps an antibody cocktail could be used that focused all of these VSGs. The problem with this approach is that there are over 1000 VSGs, so characterizing all of them would be extremely difficult.