MolES Director Pat Stayton developing targeted ‘radical cure’ for malaria
April 22, 2019
A research team led by University of Washington (UW) Distinguished Career Professor of Bioengineering and Molecular Engineering & Sciences (MolES) Institute Director Patrick Stayton has received a grant from the Bill & Melinda Gates Foundation to develop a new therapeutic for the radical cure (prevention of relapse) of malaria.
Although there has been promising progress in the development of 8-aminoquinolone drugs for the prevention of malaria relapse, patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) are at significant risk of developing hemolytic anemia when treated with these drugs. G6PD deficiency is a genetic disorder affecting roughly 400 million people and is especially prevalent in areas where malaria is common. Thus, the ability to safely and effectively treat patients with G6PD deficiency is an ongoing obstacle to eradicating malaria.
Over the next year, the team will build on proof-of-concept studies previously funded by the Gates Foundation to develop a treatment for malaria relapse that can be administered regardless of the G6PD status of the patient.
“We’ve devised a targeted prodrug – essentially a drug that only becomes activated upon reaching its designated target tissue – to bypass the induction of hemolytic anemia in G6PD patients,” said Stayton, an expert in the development of therapeutics and drug delivery systems. “For the project’s next phase, we assembled an accomplished team with the most advanced, clinically-relevant models of G6PD deficiency and an activity malaria model to test the prodrug’s therapeutic index which compares therapeutic effectiveness versus toxicity. We are grateful for the Gates Foundation’s support and considerable malaria technical expertise – they have been instrumental to advancing this work.”
The multi-institutional team includes University of Colorado Denver professor Rosemary Rochford, researchers led by Qigui Li at the Walter Reed Army Institute of Research, and Pharmaron, a contract research organization based in California. The Stayton team is led by senior research scientists Selvi Srinivasan and Debashish Roy, together with research scientist Vladimir Vlaskin and postdoctoral senior fellows Clare LeGuyader and Thomas Chavas.
Malaria relapse is caused by the parasite Plasmodium vivax which, like other malaria causing parasites, infects the blood through a mosquito bite to cause an acute malaria episode. But unlike other malaria causing parasites, P. vivax can remain dormant in the liver (in a form known as hypnozoite) for weeks, or even years, before reawakening to invade the bloodstream and give rise to disease symptoms once again. The term ‘radical cure’ refers to the complete elimination of malaria parasites from the body, specifically the elimination of hypnozoites.
Geographically, P. vivax is the most widely distributed cause of human malaria. An estimated 14 million people in the world are infected with P. vivax and some 2.5 billion live in areas where they are at risk of becoming infected.
Last July, for the first time in over 60 years, the Food and Drug Administration approved a new drug, tafenoquine (TQ), as a radical cure for P. vivax malaria. Originally synthesized by scientists at Walter Reed Army Institute of Research in the 1970s, GalaxoSmithKline (GSK) collaborated with Medicines for Malaria Venture (MMV) to develop tafenoquine for the treatment of liver stage malaria. The established medication commonly used to eliminate hypnozoites and prevent relapse is called primaquine (PQ). Primaquine is administered daily for 14 days whereas GSK’s tafenoquine drug Krintafel can be administered via a single dose, a difference that could improve compliance and reduce the burden of P. vivax. Following the approval of Krintafel, the FDA also approved 60 Degrees Pharmaceuticals’ Arakoda tafenoquine tablets for the prevention of malaria as a prophylaxis.
“This is an incredibly exciting time in malaria research, particularly the radical cure field,” said Stayton. “The successful development and approval of tafenoquine is a remarkable achievement – a sign that we’re entering a new era in the treatment of malaria, and an inspiration to all of us working to eradicate malaria.”
While the approval of tafenoquine signifies tremendous progress in the treatment of malaria relapse, additional therapies are still needed. Likely due to their similar chemical structures, both primaquine and tafenoquine cause hemolytic anemia in P. vivax patients with G6PD deficiency. As a result, patients need to be tested for G6PD deficiency before receiving treatment, but testing for G6PD deficiency is not available in many settings.
Stayton’s team may have a solution. They devised a novel drug delivery system that specifically targets primaquine or tafenoquine to the liver, to increase the potency of the drugs while avoiding the induction of toxic side effects in G6PD patients.
“Through molecular engineering we created what we call ‘drugamers’ that exploit a novel polymer engineering approach to incorporate primaquine or tafenoquine into a degradable nanocarrier,” said Stayton. “This degradable nanocarrier releases the drug only once it has been delivered to and taken up by a liver cell, limiting systemic metabolism of the drug and in turn reducing unwanted adverse effects.”
If sufficient preclinical success is demonstrated, Stayton hopes to test drugamer candidates in more advanced animal models and, with continued success, eventually conduct trials in humans.