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In vitro Diagnostic for the Liver Flukes Opisthorchis viverrini and Clonorchis sinensis



388 In vitro Diagnostic for the Liver Flukes Opisthorchis viverrini and Clonorchis sinensis

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years



The liver flukes, Opisthorchis viverrini and Clonorchis sinensis, are known to cause cholangiocarcinoma (CCA), a type of liver cancer that develops within the bile duct. These species of flukes are classified as Group I carcinogens by the International Agency for Research on Cancer (IARC). They are primarily transmitted to humans by eating raw or undercooked fish, and it is estimated that approximately 45 million people worldwide are infected. Although CCA is generally considered a rare disease with a worldwide incidence of 2-3 cases per 100,000 people, the incidence in areas where liver fluke infections are prevalent (e.g., Southeast Asia and China) is up to 85 cases per 100,000 people. US veterans who served in Vietnam have shown an increasing incidence of CCA, and a pilot study conducted by the Veterans Administration (VA) suggests that 25% of Vietnam veterans were infected with C. sinensis during their military service. This statistic might not be entirely accurate since the VA test was not designed to detect O. viverrini, the more prevalent fluke in South Vietnam. The VA test, as well as other tests developed in academic laboratories, suffers from low sensitivity and specificity. Detecting fluke infections is the rate-limiting step in intervention as effective treatment is available for fluke infections; therefore, the lack of a reliable test represents an unmet need worldwide and is potentially very important for screening the millions of US veterans who served in southeast Asia. Additionally, the CDC estimates that 10-15% of US immigrants from Asian countries may have been infected. To address this need, this SBIR solicitation will support the development of diagnostic tests or kits to detect chronic and early/mild acute liver fluke infections.

Project Goals

The primary goal of this contract solicitation is to facilitate the commercial development of a diagnostic test(s) to detect chronic and early/mild acute liver fluke infections caused by O. viverrini and C. sinensis and thereby decrease the incidence of CCA and possibly also hepatocellular carcinoma (HCC). For each of the other infectious Group I carcinogens associated with human cancers (i.e., hepatitis B and C, Helicobacter pylori, HPV, EBV), FDA-approved diagnostics are available. Currently, the standard diagnostic tool for liver fluke infection is a fecal smear and either direct examination or variations using concentration to increase the number of eggs within the sample. The sensitivity of these tests is low and requires repeated testing over several days to detect true positives and is not routinely performed in the US. Egg production of the flukes can vary widely (from zero to thousands), depending on adult fluke load as well as the length of the infection. Thus, the limit of detection of these

techniques precludes reliable diagnosis of early, mild, chronic and resolved (please see discussion below) infections. The specificity of these tests is also low since the eggs of many helminths look similar.

The average lifespan of C. sinensis within the human host is reported at 30 years and that of O. viverrini is estimated to be on the same order. Consequently, Vietnam veterans could theoretically fall into one of two categories: (1) those with low level chronic infections, and (2) those with infections that eventually resolved without drug treatment. Diagnostic approaches for Vietnam veterans may be different than for patients with early or mild acute disease.

This solicitation is intended to result in a diagnostic test for O. viverrini and C. sinensis without any preconceived biases regarding the best approach. Therefore, the proposed platform/approach may utilize any technology capable of meeting the stated goals of this contract solicitation. Diagnostic tests that are useful in developed countries where lab equipment is not limited are welcomed, as are simple point-of-care diagnostics that can be utilized in the absence of such equipment.

The short-term goal of this topic is to develop a CLIA diagnostic test or kit to detect chronic and early/mild acute liver fluke infections. The long-term goal is to develop an FDA-approved diagnostic test.

Acceptable technologies/approaches under this contract topic may include, but are not necessarily limited to:

• Antibody based assays

• Point of care diagnostics using synthetic biology

• Biosensors

• Paper or micro-fluidic devices, lab on a chip, dynamic biomaterials

Please note that the following are NOT considered appropriate for development under this contract topic:

Studies focusing solely on measuring liver fluke infections in animal models

• Development of assays and/or technologies for research use only

• Developing diagnostics to other species of liver flukes, such as Fasciola hepatica

General studies to identify biomarkers associated with O. viverrini and C. sinensis infection

Phase I Activities and Deliverables

Develop a working diagnostic assay and/or prototype point-of-care diagnostic device that can identify the target pathogens (O. viverrini and C. sinensis) in low biomass infections.

• Determine the sensitivity, specificity and other performance characteristics (e.g. limit of detection, cross reactivity with other helminth infections, reproducibility, feasibility for newly infected, chronically infected, and resolved infected clinical samples, test stability) of the diagnostic test.

• Conduct initial testing using samples from animal models and/or preferably on patient isolates to demonstrate feasibility.

• Offerors may need to establish a collaboration or partnership with a medical facility or research group in the US or overseas that can provide relevant positive control and patient samples; offerors must provide a letter of support from the partnering organization(s) in the proposal.

Phase II Activities and Deliverables

Activities leading to the ultimate development of an FDA approved diagnostic test, including but not limited to:

Develop a well-defined test platform under good laboratory practices (GLP) and/or good manufacturing practices (GMP).

• Perform scale-up and production for multi-site evaluations (with at least one independent CLIA-certified laboratory) using clinical isolates.

• Demonstrate suitability of the test for use in the clinic.

• Establish a product development strategy for FDA regulatory approval (as appropriate).

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