Screening and treatments for the mucopolysaccharidoses
Date
2020
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
With an incidence rate of approximately 1:25,000, the mucopolysaccharidoses (MPS) are a heterogenous family of genetic disorders that, when taken collectively, account for the most common type of lysosomal storage (LSD) disorder in the world. Caused by a deficiency in one of several catabolic enzymes responsible for breaking down negatively charged polysaccharides glycosaminoglycans (GAGs), MPS disorders lead to progressive GAG accumulation. Symptoms of MPS disorders vary widely but often include physiological and neurological symptoms. Age of diagnosis tends to negatively correlate with severity of eventual disease phenotype. ☐ Current treatments for MPS disorders including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are ineffective on treating skeletal disease symptoms. In MPS IVA, treatment of these skeletal symptoms is particularly important as there is no neurological decline and thus, skeletal abnormalities make up the primary symptoms of the disorder, even in the case of more severe patients. ☐ In this study I established pre-clinical efficacy of a new gene therapy treatment for MPS IVA in two MPS IVA murine models (Chapter 3). I conducted this study utilizing adeno associated viral (AAV) vectors as the method of delivery for the human N-acetylgalactosamine-6-sulfatase (hGALNS). I showed efficacy of this treatment in tissues of MPS IVA model mice. In addition I showed decreased GAG storage in treated mice and I determined greater efficacy in mice treated with the ubiquitous CMV enhancer/ chicken beta actin (CAG) promoter as compared to both higher and lower doses of the liver specific thyroxine binding globulin (TBG) promoter. ☐ I continued the work of establishing efficacy of a liquid chromatography tandem mass spectrometry (LC-MS/MS) newborn screening (NBS) method for MPS I and MPS II for early diagnosis (Chapter 4). I used this method in tandem with alpha-L-idruonidase (IDUA) and iduronate-2-sulfatase (IDS) 4-methylumbelliferone (4-MU) enzyme assays conducted by collaborators to demonstrate the increased efficacy of a two-tiered method of NBS for MPS disorders. ☐ Finally, I worked to help improve knowledge of safety and efficacy of current and potential treatments by establishing safety in pentosan polysulfate (PPS) treatment of MPS II and showing lack of efficacy of current treatments for MPS IVA as determined by bone growth and activity of daily living (Chapter 5). In an effort to determine the most complete picture of such novel treatments in MPS IVA, I worked to establish a new MPS IVA GALNS knockout (KO) murine model (Chapter 6). ☐ Methodologies established in these studies address critical deficits in treatment and diagnoses for MPS patients. Early, multitiered newborn screening allows for preemptive diagnosis before clinical symptoms are present and likely a greater efficacy of treatment. The assessment of efficacy and safety of currently available treatments will inform knowledge on patient treatments and along with establishment of effective animal models, help pave the way for new and effective treatments. Finally, I will show the success of AAV8 mediated gene therapy in treating skeletal abnormalities. The success of this treatment provides evidence for a new treatment that might ameliorate the worst symptoms of these disorders, giving patients and their caregivers an improved quality of life (QOL).
Description
Keywords
Gene therapy, LC-MS/MS, Lysosomal storage disorder, MPS, Newborn screening, Skeletal dysplasia