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A new answer for amoeba treatment
SAN DIEGO—Rare diseases are becoming more popular targets because they offer a niche with limited competition, but what about a condition so rare that it’s only affected about 150 people in the last 55 years? To a research team at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, that’s still enough of a problem to be worth investigating.
The problem at hand is an amoeba known as Naegleria fowleri, which is generally found in warm bodies of water, such as swimming pools, lakes and rivers. When it does infect people—which occurs primarily “when contaminated water enters the body through the nose,” according to the U.S. Centers for Disease Control and Prevention—it causes severe primary amebic meningoencephalitis (PAM), a “brain-eating” disease that is nearly always fatal. No treatments exist save for a trial-and-error approach at administering general antifungal drugs. Fortunately, N. fowleri infection is very rare; the CDC reports that between 2008 and 2017, only 34 reported infections occurred in the United States.
The danger of N. fowleri infection is not its prevalence, however, but its severity. Between 1962 and 2017, only 143 reported infections have been recorded. Of those, only four people have survived. The CDC notes that two people who were infected survived thanks to miltefosine, an investigational drug that was administered with other drugs and paired with “aggressive management of brain swelling.”
A research team led by senior author Dr. Larissa Podust, associate professor at Skaggs School of Pharmacy, and co-first authors Dr. Anjan Debnath, assistant professor at Skaggs School of Pharmacy, and Dr. Wenxu Zhou of Texas Tech University, set out to find some better options.
The team started their search for new potential treatments by examining the sterol biosynthesis pathway of the amoeba, which is a set of enzymes that comprise the outer membrane. The researchers identified and inhibited three such enzymes that could prove to be promising drug targets, one of which was a sterol isomerase. The enzyme resembles one of the human receptors in the brain that is associated with neurological conditions such as depression, amnesia, pain and addiction. In the search for approved drugs that inhibit those enzymes, Podust and colleagues found 13 drugs that were more potent than miltefosine. Among those were tamoxifen, a selective estrogen receptor modulator for preventing and treating breast cancer, and the antidepressant Prozac, which is a selective serotonin reuptake inhibitor.
The approved drugs the team tested were found to be significantly more effective than miltefosine—while 54.5 micromolar (µM) of the drug is needed to half the growth of half a sample of N. fowleri in a dish, only 5.8 µM of tamoxifen and 31.8 µM of Prozac were needed to achieve the same effect. A combination of a lower dose of tamoxifen and other drugs that inhibit different enzymes in the sterol biosynthesis pathway resulted in the inhibition of 95 percent of N. fowleri in a test dish.
Repurposing drugs for new indications offers a variety of benefits, chief among them being shortened time to approval, as safety data from human trials has already been established. For indications such as this where drugs need to cross the blood-brain barrier, a known stumbling block, it’s especially helpful.
“Not many drugs can cross the blood-brain barrier,” said Podust. “Even if a drug can inhibit or kill the amoeba in a dish, it will not work in a host animal if it does not make it into the brain. That’s why we started with drugs known for their brain effects.”
Debnath tells DDNews that the team plans to further explore both the 13 drugs they’ve looked at so far and other drugs that could treat the amoeba.
"We're taking two approaches. In addition to these drugs, we're testing several other compounds, mainly focusing on those compounds which can cross the blood-brain barrier,” he says. “This infection happens in the brain, and that is the challenging part—how to find a drug which is brain-active. We are investigating the potency of blood-brain barrier-permeable drugs against Naegleria fowleri. So that is one approach we are trying, to find blood-brain barrier-permeable amebicidal drugs. Moreover, we are taking the combination approach. You can see the use of several anti-fungals, as well as miltefosine and anti-inflammatory drugs, in the current treatment regimen for Naegleria fowleri infection, so a combination therapy would be a very attractive approach."
He adds that repurposing is a “useful strategy” for this infection, noting that “Since Naegleria fowleri infection is rare and highly fatal, a Phase 2 clinical trial is almost not feasible. But these drugs are approved by the FDA, so they have undergone Phase 1 safety trial. If we can show that these drugs are efficacious in an animal model of Naegleria fowleri infection, it is possible that the CDC or FDA may recommend the compassionate use of these drugs in PAM patients."
"We are one of about six university centers in the world currently conducting drug discovery research with live Naegleria fowleri that's in culture … and based on current publications, we're the only one in the U.S. with an in-house animal model of this infection. And we have a very strong interdisciplinary team that includes Dr. Larissa Podust, a structural biologist. So we're all working together, and our center is well equipped to develop any new drug for this fatal infection,” says Debnath.