Farber disease is a very rare and very severe lysosomal storage disorder that most commonly presents in the first few months of age. A deficiency of lysosomal acid ceramidase (AC) activity results in the accumulation of ceramide in lysosomes causing multiple clinical manifestations that are painful and severely impact quality of life. The illness is progressive, and often leads to death within the first few years. The propose project will characterize a murine model we generated that harbors a human mutation in the AC gene. Preliminary observations show that disease progression and clinical manifestations in our current model highly correlates with what is observed in humans. Furthermore, this project will carry out correction of the mouse model using two different transplantation platforms: (1) bone marrow transplantation, and (2) LV- modified ex vivo-targeted HSC therapy. Results acquired from gene therapy correction of our Farber model will provide insight for the development of novel therapies for this currently incurable disease in humans. This model will also impact research on the understanding of ceramide metabolism, signaling, bioactive properties, and role in cancer.
Specific Aims : (1) To test the hypothesis that a novel 'knock-in'mouse model harboring a conserved human DNA mutation will recapitulate Farber disease pathophysiology. (2) Explore the effects of bone-marrow transplantation and LV-mediated overexpression of human AC in hematopoietic stem/progenitor cell transplants in Farber mice as treatments for this disorder. Research Design and Methods: (1) We have very recently generated a novel murine model for Farber disease. Viability and morphological abnormalities will be analyzed. MEFs and tissues from various organs will be collected from normal, heterozygous, and homozygous mice to assay for AC enzyme activity and ceramide levels. Structural changes on the cellular level will be compared using EM. Dr. Walkey's group will also assess neurological structure and functional impairment. (2) We will engineer a novel LV that directs the expression of human AC along with a cell fate control cassette to ensure safety of the vector. We will attempt bone marrow transplantation and cell-directed gene therapy of Farber mice using a clinically relevant treatment schema. Syngeneic HSCs and HPCs modified using the novel LV will be infused into fully ablated Farber mice. Animals will be followed over time and manifestations of Farber disease will be analyzed as in Aim 1.

Public Health Relevance

The proposed project aims to use a newly generated mouse model of Farber disease to test novel lentivirus vector-based genetic modification platforms as potential therapeutic options. The newly generated Farber mouse model highly correlates with human Farber disease in terms of disease progression and clinical manifestations. The proposed research will ultimately lead to novel therapeutic interventions for this devastating and incurable condition. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Morris, Jill A
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University Health Network
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M5 2-M9
Dworski, Shaalee; Lu, Ping; Khan, Aneal et al. (2017) Acid Ceramidase Deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. Biochim Biophys Acta Mol Basis Dis 1863:386-394
Sikora, Jakub; Dworski, Shaalee; Jones, E Ellen et al. (2017) Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. Am J Pathol 187:864-883
Dworski, Shaalee; Berger, Alexandra; Furlonger, Caren et al. (2015) Markedly perturbed hematopoiesis in acid ceramidase deficient mice. Haematologica 100:e162-5
Jones, E Ellen; Dworski, Shaalee; Canals, Daniel et al. (2014) On-tissue localization of ceramides and other sphingolipids by MALDI mass spectrometry imaging. Anal Chem 86:8303-11
Alayoubi, Abdulfatah M; Wang, James C M; Au, Bryan C Y et al. (2013) Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med 5:827-42