Proposal for the Supplement to the American Journal of Tropical Medicine and Hygiene: "The intolerable burden of malaria: what's new, what's needed". Each year, up to 2.7 million deaths due to malaria and over one billion episodes of clinical illness meriting antimalarial therapy occur in Africa. The papers in the supplement will examine the methodologies used to calculate the global burden of disease and the place of malaria within it; review the contribution of some of the clinical components of the burden (i.e. anemia, neurological sequelae); assess the impact of mosquito transmission on morbidity and mortality; consider experiences in monitoring the burden through the Roll Back Malaria Program; and, review approaches for determining the economic toll take by malaria. The supplement will cover the costly role of epidemics, the many social and economic burdens due to malaria, all of which are impeding development, cost-effectiveness of newer control methods, and a research agenda and other focused activities helping define malaria's toll more precisely. This collection of papers, many of which were presented at a symposium at the 3rd Multilateral Initiative on Malaria (MIM) Pan African Conference held in November 2002 in Arusha, Tanzania, will complement and go beyond a companion supplement to the American Journal of Tropical Medicine and Hygiene on the malaria burden published in 2001. The second supplement to be published by the American Journal of Tropical Medicine and Hygiene: "The intolerable burden of malaria: what's new, what's needed" is intended to go beyond the first set of papers, particularly in economics. This supplement will include more than 26 papers on the burden of malaria, 18 of which were presented in Arusha. Publication of the second supplement is scheduled provisionally for late 2003.

My research aims to further define the pathological biochemistry of RPGR-mediated X-linked Retinitis Pigmentosa (RPGR/XLRP), an inherited retinal dystrophy that causes blindness and has no treatment. I hope better understanding of disease mechanism will help identify potential therapeutic options. Photoreceptor outer segments have evolved from primary cilia to compartmentalise the visual pigment rhodopsin into an elaborate structure of folded membranes, known as discs, enabling normal vision. Failure of disc morphogenesis results in photoreceptor degeneration; the hallmark of Retinitis Pigmentosa (RP). Recent work suggests that photoreceptor disc formation is an actin-mediated process, but the exact mechanism by which they form is unknown. RPGR mutations account for 20% of RP and my previous work suggests RPGR regulates actin turnover in the photoreceptor connecting cilium. I hypothesise that RPGR acts as an assembly platform that recruits actin binding proteins to promote morphogenic membrane curvature at the distal connecting cilium, resulting in disc formation. My work in this application will examine my hypothesis. I will use animal models of RPGR/XLRP and endogenously tagged proteins to determine the biochemcial processes that underpin the disease using a combination of molecular biology, novel interactomic experiments and super-resolution imaging. Retinitis Pigmentosa (RP) is an inherited eye condition that causes death of the light-sensing photoreceptor cells at the back of the eye, causing blindness. Mutations in several genes cause RP, which has no treatment. Mutations in one particular gene, RPGR, causes 20% of all cases and results in a particularly severe form of disease. The reason no treatment exists for RPGR-related disease is that we don’t know the function of RPGR in the light-sensing photoreceptor cells. Previous work by myself (and others) suggests it helps to regulate the inner skeleton of the photoreceptor cells. If we knew exactly what role it played, we might be able to design treatments for the disease. My work focuses on attempting to fully uncover RPGR’s function in the photoreceptor. I hope one day this will lead to us correcting the errors that lead to photoreceptor death, thus preventing visual loss in this devastating disease.

Over 400 million people are infected with hookworms, resulting in significant morbidity, mostly from chronic anemia. Our Controlled Human Hookworm Infection (CHHI) model could accelerate the development of a human hookworm vaccine (HHV) to prevent such infection. This CHHI model has been shown to be safe, well-tolerated, and reliably induce patent infection in hookworm-naïve adults infected with Necator americanus third-stage larvae (NaL3) produced at the Good Manufacturing Practice (GMP) facility at George Washington University. We propose to transfer NaL3 production technology to Brazil to conduct: (1) Necator Donor Program for the continual production of NaL3 in Brazil; (2) Dose-escalation study in adults infected with Necator to determine a dose of NaL3 that is well-tolerated and reliably induces patent infection; (3) Hookworm vaccination-challenge trial of two lead HHV antigens: Glutathione S-transferase-1 (Na-GST-1) and Aspartic Protease-1 (Na-APR-1), which have proven safe, well-tolerated, and immunogenic in Phase 1 trials in the USA and Necator-endemic areas of Brazil and Gabon. Our proposal will establish a GMP facility in Brazil for production of NaL3 to conduct such controlled human infection studies. Importantly, this project establishes a platform for rapid assessment of vaccines, therapeutics and diagnostics for hookworm, in a population significantly affected by this helminth.