(2ji) Improving Gene Therapy Manufacturing and Vector Transduction Efficiency through Capsid Engineering

Gene therapy has emerged as a highly promising therapeutic approach for addressing a wide range of human diseases. In essence, gene therapy involves introducing modified genetic material into human cells as a means of treating or curing these diseases. Among the various methods of delivering genes, recombinant adeno-associated virus (rAAV) has gained prominence as a highly effective vector due to its specificity, efficiency, and safety. However, the large-scale production of rAAV vectors still poses challenges in terms of ensuring product integrity and potency. My group aims to use capsid engineering to enhance the stability of the product, reduce heterogeneity, and improve the efficiency of vector transduction.

Research & Professional Background:

PhD Student – University of Virginia (2011-2016):

During my PhD study in Giorgio Carta's group at the University of Virginia, my research focused on investigating the molecular interactions that contribute to the unfolding and aggregation of monoclonal antibodies on the surface of certain cation exchanger resins. By employing Confocal Laser Scanning Microscopy (CLSM), I was able to uncover a correlation between the aggregation behavior and the distinct kinetics of protein transport and binding within tentacle-type resins. Additionally, through the application of Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS), I was able to identify the unfolding regions of the monoclonal antibody during its adsorption onto the resin.

Postdoc – University of Delaware (2016-2018):

Motivated to address challenges in downstream purification of biological products through upstream cell line engineering, I chose to pursue a postdoc at the University of Delaware under the guidance of Professor Kelvin Lee and Professor Abraham Lenhoff. One aspect of my work involved the utilization of CRISPR technology to specifically target and eliminate a host cell protease known to cause degradation of therapeutic proteins during biomanufacturing processes. This approach demonstrated my proficiency in genetic engineering techniques and their application in enhancing the quality of biopharmaceutical products.

Scientist in Biopharmaceutical Industry - Teva and BMS (2018-2022):

Leveraging my expertise in protein purification and genetic engineering, I joined Teva Pharmaceuticals as a scientist specializing in process development for therapeutic antibodies. In this role, I designed multicolumn continuous chromatography processes for pipeline molecules to improve productivity and reduce manufacturing costs. Following my work at Teva, I transitioned to Bristol Myers Squibb (BMS) as a senior scientist, assuming the role of downstream lead responsible for process development for a key pipeline molecule. Working closely with cross-functional teams encompassing cell line engineering, upstream development, and analytical development, I actively addressed challenges encountered during the biomanufacturing processes. Furthermore, I delved into the investigation of binding behaviors exhibited by monoclonal antibody and fusion protein therapeutics in Protein A chromatography by employing a multi-faceted approach encompassing molecular, resin particle, and column-level analyses. Through these industry experiences, I have acquired a comprehensive understanding of the inner workings of the biomanufacturing industry and a recognition of the practical limitations that necessitate further fundamental research.

Research Scientist – MIT (2022-Present):

Motivated by the need to tackle practical challenges in biomanufacturing, I decided to join Richard Braatz's group at MIT as a research scientist specializing in biomanufacturing process modeling. In this role, I am leading a team comprising graduate students and postdocs, collaborating to develop hybrid models that integrate both mechanistic and machine learning approaches. Our primary objective is to predict and control the glycosylation profiles of monoclonal antibodies manufactured in Chinese Hamster Ovary (CHO) cell culture. Through these research experiences, I am gaining expertise in parameter estimation, model-based design of experiments, and the implementation of process control strategies in biomanufacturing.

Research Vision:

Building upon my diverse background encompassing industry and academic research, as well as expertise in genetic engineering, downstream purification, and modeling, I am uniquely equipped to tackle challenges from various perspectives. While I have gained extensive experience working with traditional therapeutic biological products like monoclonal antibodies and fusion proteins, I am now eager to embrace the opportunities presented by the emerging field of gene therapy. My research group will focus on exploring capsid engineering strategies to address key challenges. Specifically, we will pursue research in the following directions: (1) Improving product stability and enabling efficient separation of empty and full capsids, (2) Reducing vector heterogeneity arising from post-translational modifications of capsid proteins, (3) Enhancing vector transduction efficiency by optimizing capsid protein-glycan receptor interactions.

Teaching Interests

During my doctoral studies at the University of Virginia, I had the opportunity to serve as a teaching assistant (TA) for the chemical engineering senior lab. In this role, I guided and mentored undergraduate students as they learned to develop and optimize process conditions to produce a recombinant protein. In addition to my TA responsibilities, I also served as a tutor for the Protein Chromatography Short Course. This course catered to process engineers from the biopharmaceutical industry who were eager to learn the fundamentals of chromatography process development. This opportunity allowed me to bridge the gap between academia and industry, equipping professionals with valuable knowledge applicable to their work.

During my four-year industry experience, I continued to contribute to education and knowledge dissemination. As a tutor for the Industrial Bioprocessing Course at the University of Massachusetts Lowell, I taught case studies related to the biomanufacturing processes of monoclonal antibodies. Furthermore, I served as a guest lecturer for the Chemical & Biomolecular Separation course at Johns Hopkins University. During my lecture, I shared insights on the current status, challenges, and future prospects of downstream processing technology.

Drawing upon my past teaching and research experiences, I am well-prepared to instruct any core chemical engineering course, with a particular enthusiasm in Separations and Transport Phenomena. These areas align closely with my research and industry background, allowing me to offer students practical insights and real-world applications. Moreover, I am enthusiastic about developing elective courses that delve into chromatographic separations and advanced biomanufacturing, catering to the evolving needs and interests of students in these research areas.