Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment.
Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Rhizopus oryzae cause life-
threatening invasive candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and murormycosis,
respectively. Patients at the greatest risk of developing these IFDs have weakened immune systems such as
HIV positive individuals. The vulnerable population is increasing due to increasing numbers of
immunosuppressed individuals receiving stem cell or organ transplants. In the U.S. medical costs for these
three IFDs exceed $5 billion dollar per year. An infected individual’s medical cost often exceed $100,000.
Patients are treated with various antifungal drugs, but all antifungals have serious limitations due to human
organ toxicity, the lack of sufficient fungicidal effect at safe doses and safely limited treatment periods, and the
emergence of resistant fungi. Even with treatment, one-year survival is only 1% to 90%, depending upon the
patient population. Few new drugs have gained acceptance in the last 20 years. We created a transformative
technology in which almost any antifungal drug may be delivered specifically to the fungal cell wall and/or their
secreted exopolysaccharide matrices to increase drug efficacy by orders of magnitude. This technology and
the conceptual framework supporting it meet the critical need for dramatically improved antifungal therapeutics.
We have employed the carbohydrate recognition domains of the C-type lectin receptors Dectin-1 and
Dectin-2 to target liposomal packaged antifungals to fungal glucans and mannans. Antifungals such as
Amphotericin B packaged in liposome penetrate the endothelium, have longer half-lives and less infusion
toxicity than detergent solubilized drugs. We have remarkably strong in vitro data showing that Dectin-1- and/or
Dectin-2-targeting of Amphotericin B-loaded liposomes improved binding efficiency to these four diverse fungal
species 100-fold over untargeted liposomes and killed three species 10- to 100-times more efficiently. The
deliverables of this high-risk high-reward proposal include (1) demonstrating that Dectin-3 in combination the
other Dectins expands fungal cell targeting capabilities, (2) generalizing the technology to the delivery of other
antifungals agents such as fluconazole and anidulafungin, and (3) assembling a preclinical data package
showing that targeted antifungal-loaded liposomes have increased efficacy in mouse models of invasive
candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and pulmonary mucormycosis. We believe we
will create a paradigm shift in the antifungal pharmaceutical industry.
We have an established team of scientists already combining their expertise in diverse areas of science
necessary to carry out these experiments. We have developed an experimental platform to rapidly innovate
and reiteratively test fungal cell specific targeting of antifungals that may be used to treat diverse life-
threatening fungal infections and milder fungal infections of eyes, skin, toenails, and biomedical devices.