Gene Therapy for MPS IV A in a Novel Porcine Model of the Disease

Project Summary This project centers on addressing the challenges posed by MPS IV A, a rare lysosomal storage disease caused by a deficiency in the GALNS enzyme due to mutations in the GALNS gene. Existing treatments, such as enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT), fall

short in effectively managing the severe skeletal manifestations of this condition. To overcome these limitations, the study aims to create a large animal model of MPS IV A and investigate the potential of gene therapy as a more effective treatment approach. The research comprises three key goals across two aims:

1. Generating a Porcine Model of MPS IV A: Using previously generated GALNS knockout lines, a porcine model with GALNS deficiency will be made. The animals will be characterized for enzyme deficiency, accumulation of keratan sulfate, skeletal defects, and cardiac anomalies. This model will serve as a

valuable tool for understanding the disease's biology and developing genetic therapies. 2. Comparative Analysis of AAV and Lentiviral Gene Therapy: The research aims to assess the effectiveness of two gene transfer methods, adeno-associated virus (AAV) and lentiviral vectors, in treating MPS IV A in mouse models. This comparative study will provide insights into the potential of

both approaches in preventing metabolic and skeletal diseases associated with MPS IV A. 3. Advancing Genetic Therapies for MPS IV A: The project explores the novel approach of using autologous hematopoietic stem cells (HSCs) transduced with a lentiviral vector containing the human GALNS sequence to treat MPS IV A. This method offers the potential for high systemic levels of

GALNS and may bypass the risks associated with allogeneic HSCT. The outcomes of this research are expected to contribute significantly to understanding MPS IV A and developing more effective therapies. The creation of a large animal model will enable researchers to closely mimic human disease conditions, and the comparative analysis of gene therapy methods will inform future

treatment strategies. Overall, this work holds promise for improving the lives of individuals affected by MPS IV A by advancing the development of gene therapeutics.