According to new research, parasites that are responsible for a disfiguring skin disease that affecting around 12 million people worldwide may have matched their ability in vaccinations developed using CRISPR gene-editing technology.
Phase 1 human trials are set to begin later this year with a vaccination designed to relieve infection byLeishmania major, the parasite species that causescutaneous leishmaniasisin tropical and subtropical regions in the Eastern Hemisphere.
The same research team, led by Abhay Satoskar, a professor ofpathology at The Ohio State University College of Medicine, has developed a CRISPR technology to target Leishmania mexicana, the species of parasite found in South, Central, and North America.
The vaccination, which was created with a mutated live parasite, posed no threat of causing skin depositions and provided long-term infection prevention.
This New World species has developed a more chronic infection that will not, unlike skin lesions generated by theL. majorinfection. Researchers expect theL. majormutant parasite vaccine to be effective against theL. mexicanaspecies, but have developed the second vaccine as a backup and to see if their technique might affect the more virulent organism.
Our goal was to see if this approach, which is removing a particular gene, would break this tough cookie, which has always been a problem. Satoskar, a professor ofmicrobiology at Ohio State, believes it is not an easy parasite. We should be able to use theL. majorvaccine in the New World. If it fails, we have a plan b.
The research is published in the journalNPJ vaccines.
In both vaccines, the team applied gene-editing technology to the centuries-old Middle Eastern technique of leishmanization deliberately introducing the live parasite to the skin to create a small infection that, once healed, leads to life-long immunity against further illness.
One question we had was, is leishmanization even possible withL. mexicana, which normally does not self-resolve? We''re talking about two leishmania species, and they cause the same disease, but the clinical outcome and response to treatments differ, according to Satoskar. Even CRISPR might not have worked, because this species has different molecules, proteases, and enzymes.
Researchers used the most advanced technology to alter the genome ofL. mexicana, remove centrin, the gene that codes for a protein that supports cell division, and inactivated an antibiotic resistance marker gene that is introduced into the parasite as part of the knocking out centrin.
These parasites may cause infection by hijacking immune cells and using host cells to replicate indefinitely. Experiments in immune cell cultures showed that the mutant parasite could enter cells and make limited copies of itself, but not enough to cause symptoms.
The study showed in mice that the vaccination is effective, causing no skin irritations in animals who are susceptible to the disease. In addition, researchers used an needle challenge to the ear, a technique to mimic a sand fly bite. Leishmania is transmitted through the bite of infected sand flies in humans and animals.
Vaccinated mice maintained their skin leions unlike the unvaccinated control group, but the number of parasites at the infection site was kept at bay, and the protection was extended over ten weeks.
The immune response obtained by vaccination with the New World species has differed dramatically from the type of response produced by the previous vaccination, according to researchers. Using theL. majorvaccination, pro-inflammatory proteins have been increased to protect themselves. Instead, TheL. mexicanavaccine suppressed anti-inflammatory proteins.
The parasites are different, and the mechanism by which they protect them is absolutely different, according to Satoskar. It''s a good balance. Both work.
Researchers are working on vaccines to help scientists understand a range of conditions to prevent diseases that can lead to disfigurement, disability, social stigma, and discrimination. Using a vaccine, the researchers predict, would cost less than $5, compared to the $100 to $200 cost for treatment in the hardest-hit countries, which requires long-term medication injections, which result in poor patient compliance. parasites may also develop resistance to the medications, causing inflammation to occur.
Visceral leishmaniasis affects organs and is fatal if left untreated. However, theL. majorvaccine may also be used to prevent this more severe form of the disease, but the team has developed a CRISPR technique to develop a vaccination with theLeishmania donovaniparasite that causes visceral leishmaniasis.