Mass Spectrometry Based Analysis of Protein N-Glycosylation in Biomarker Discovery and Gene Therapy with the Study Models-Hemophilia A Inhibitor Development and rAAV
Date of Award
Doctor of Philosophy (PhD)
Protein glycosylation is one of the critical post-translational modifications (PTMs) and practically engaged with a wide range of physiological and biological processes. Glycosylation is the most dynamic post-translational modification and an individual's glycome changes overcome the genetic factors and get affected by environmental factors which eventually reflect his lifestyle, physiological conditions and wellbeing. The flow study, we attempted to add this information to comprehend the glycoprotein biomarker identified with inhibitor advancement and connected the glycosylation related changes to the biochemical pathway of inhibitor development against rFVIII in HA population. We performed the study with mice and human models. Plasma and IgG N-glycome examination is one of the important methodologies to identify the biomarker related to numerous conditions. The N-glycome pattern also varies in response to the treatment. The treatment-related modifications also reaffirm the observations noted in the progression of the disease. Similarly, the glycosylation can be a useful strategy to modify the protein-based drugs to enhance its mode of action. The variant of AAV can be a potential capsid engineering technique to alter the tropism and improve the gene delivery range of host cell range for engineering a better gene delivery system. The small amount of and glycan variants are difficult to detect in a complex biological mixture, which may require various enrichment strategies, and sample preparations help to enhance the detection sensitivity in mass spectrometry. Due to the with the development of state-of-the-art mass spectrometry (MS) technology, we tried to identify N-glycan biomarkers related to inhibitor development in HA. Also, we decided to study the response of the patient after emicizumab. Additionally, we identified N-glycosylation in rAAV-8, which can be a potential direction for future capsid engineering.
Aloor, Arya, "Mass Spectrometry Based Analysis of Protein N-Glycosylation in Biomarker Discovery and Gene Therapy with the Study Models-Hemophilia A Inhibitor Development and rAAV." Dissertation, Georgia State University, 2020.
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