Amprion, Inc. — Department of Health and Human Services SBIR Phase I: 101

Description

ABSTRACT Human prion diseases are infectious and invariably fatal neurodegenerative diseases including sporadic Creutzfeldt Jakob disease sCJD the most common form and variant CJD vCJD which is associated to consumption of cattle meat infected by bovine spongiform encephalopathy Currently there is not sensitive objective and non invasive biochemical diagnosis for these diseases and even less a procedure to detect people incubating the disease in the pre symptomatic period This is a major problem for public health because prion diseases are known to transmit iatrogenically between human to human and because due to the long pre symptomatic stage of the disease which may span five decades the asymptomatic carriers far outnumber the clinically affected individuals To make the situation even more complicated the infectious agent responsible for these diseases termed prion is composed exclusively of a conformationally altered form of a naturally occurring protein named PrPSc which has the unique ability to infect individuals and propagate in the body without the need for genetic material PrPSc is not only the infectious agent and the likely culprit of neurodegeneration but also the best surrogate marker for the disease The challenge is that its quantity is high only in the brain at late stages of the disease However compelling evidences indicate that PrPSc is present in minute amounts in various peripheral tissues and biological fluids including blood This proposal is a continuation of a previously funded phase I II fast track STTR project R NS whose major goal was to develop a blood and cerebrospinal fluid CSF based detection assay for PrPSc associated with sCJD and vCJD Our strategy utilizes the protein misfolding cyclic amplification PMCA technique a pioneering proprietary technology developed in Dr Sotoandapos s lab PMCA enables highly efficient prion replication in the test tube by amplification of this process in vitro and offers a great opportunity to detect very small quantities of prions During the previous funding cycle we were highly successful to reach the main aims and milestones including the substantial optimization and improvement of the technology for human samples and the detection of PrPSc in samples of blood and urine of patients affected by vCJD with sensitivity and specificity approaching Another goal of the phase II was to obtain approval for using PMCA for disease diagnosis Currently a variation of the PMCA assay is successfully under use by the USA CJD Surveillance Center based on Cleveland OH to help the diagnosis of CJD and Amprion is receiving royalty payments for this application However given the small number of cases the diagnosis market is not profitable at this time Amprion regards the screening of the blood supply as the most relevant market for commercialization of the Companyandapos s technology Based on the success achieved during the phase I and II of this project we engaged in extensive discussions with the UK National Institute for Biological Standards and Control NIBSC the governmental organism trusted with the responsibility to validate and approve prion detection techniques in the UK and the Food and Drug Administration FDA to define the regulatory pathway to get approval for detection of prions in human blood As a result of these discussions we have agreed to a validation pathway defined by these agencies to obtain regulatory approval for the commercialization of a PMCA based assay for detection of prions in human blood samples and started the phase I of this process The main goal of this Commercialization Readiness Pilot CRP project is to complete the regulatory and market approval of our test for detecting prions in blood of people infected by the vCJD agent and to increase the throughput of the assay to handle the number of samples expected during commercialization The validation pathway includes steps namely i testing a panel of blood samples spiked with vCJD brain or spleen extracts ii a large screening of negative samples to assess specificity iii a panel of samples from non human primates infected with the vCJD agent and iv a group of samples from patients with confirmed vCJD These samples will be provided blindly by the NIBSC or the FDA The results generated in this project would lead to the development of a validated biochemical test to detect vCJD prions in human blood and the demonstration that this can be achieved before the clinical onset of the disease in asymptomatic carriers through the longitudinal studies in non human primates experimentally infected with the vCJD agent Availability of a validated methodology to screen blood for infectious prions will increase the safety of blood transfusions and potentially also products derived from human plasma Finally such a screening test could be utilized for a study of the size of the asymptomatic population of carriers i e the number of people infected with the vCJD agent who have not yet developed the clinical disease For commercialization of the validated test Amprion will establish validated reference laboratories in different geographic locations e g North America Europe Asia that can handle the centralized testing of the samples with the accuracy efficiency and safety needed for this type of assays NARRATIVE Development of a biochemical assay for the sensitive specific early and non invasive detection of prions in blood of patients affected by variant Creutzfeldt Jakob disease vCJD is a top medical priority to increase the safety of the blood supply vCJD has already been transmitted from human to human by blood transfusion and the number of asymptomatic carriers of vCJD in the UK alone is estimated to be people This project utilizes the revolutionary protein misfolding cyclic amplification PMCA technique to detect prions with extremely high sensitivity In the previous phaseI II STTR project we demonstrated that the technology permits detection of prions in blood and urine of vCJD patients with sensitivity and specificity close to The main goal of the Commercialization Readiness Pilot project is to complete the regulatory approval of our test for detecting prions in blood of people infected by the vCJD agent and to increase the throughput of the assay to handle the number of samples expected during commercialization In this project we have put together the relevant technical business and regulatory expertise secured the availability of key samples and worked with regulatory authorities in the UK and US to define the validation pathway to reach the approval of the test