A Mouse Model for the Rare Plasma Cell Disease AL Amyloidosis

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PROJECT SUMMARY/ABSTRACT This application addresses the broad Challenge Area (15) "Translational Science", and the Specific Challenge Topic 15-OD(ORDR)-101, "Pilot projects for prevention, early detection and treatment of rare diseases". In this application, we propose to develop a "second generation" transgenic mouse model of the rare disease AL amyloidosis. AL is a disease with features of a plasma cell dyscrasia, and is caused by a low grade clonal expansion of plasma cells in the bone marrow. It also has features of a protein folding disorder, in that the pathology in the disease is caused by deposition of the immunoglobulin light chains produced by the plasma cells as fibrillar proteins in tissues. This leads to organ dysfunction, organ failure, and death. Amyloidosis is recognized by Congress, in the Departments of Labor, Health And Human Services, and Education, and Related Agencies Appropriations Bill in 2005, 2006, and 2007 as a rare and understudied disorder: "The Committee encourages NIH to expand its research efforts into the amyloidoses-a group of rare diseases characterized by abnormally folded protein deposits in tissues. These diseases are often fatal and there is no known cure. Treatment involving large-dose intravenous chemotherapy followed by stem cell replacement or rescue is effective for many patients, but this procedure is risky, unsuitable for many patients, and not a cure." In 2006, the Office of Rare Diseases at NIH convened a Systemic Amyloidosis Focus Group Workshop that outlined the "Challenges and Opportunities for Systemic Amyloidosis Research," published in the journal Amyloid (Wright DG et al., Amyloid 14(2): 103-112, 2007). That report described animal models as "....a particularly critical research resource need. Such animal models offer the best chance for investigators to address fundamental questions of amyloid disease pathogenesis: e.g. the basis for tissue tropism, disease triggering conditions and genetic modifiers, as well as the role of amyloid precursor protein processing in disease expression. Animal models are also critical for the identification and development of potential therapeutics." This proposal seeks to address the unmet need for better animal models for AL amyloidosis, the most common of the systemic amyloidoses in U.S. citizens. It will build upon our initial experience generating animal models, with support of a P01 for studies of "Immunoglobulin Light Chain Fibrillogenesis". We will use a novel vector that causes the Myc oncogene to be expressed in a tissue-specific and stage-specific fashion in terminally differentiating B cells, leading to poly- and then mono-clonal expansion of plasma cells. By engineering the vector to also synthesize a human amyloidogenic immunoglobulin light chain, we hope to replicate the human disease AL amyloidosis. Mice will be characterized and used to study disease pathogenesis and treatment. To carry out this project, we will require the assistance of an additional laboratory technician, postdoctoral fellow and graduate student and will augment the use of existing Core facilities staffed by animal technicians and an expert transgenic technician.