Machine Learning Prediction of Gas Condensate Reservoir Initial Composition and Dew Point Pressure at Various Pressure and Temperatures

Research Interests

RNA therapeutics enable personalised medicine and effective treatments for rare, infectious and life-threatening diseases. A milestone of RNA therapeutics was the clinical approval of messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, administered for combating COVID-19. To attain therapeutic effects, RNA molecules are required to reach the desired target site and sufficient proteins of interest ought to be produced. To date, a multitude of delivery systems have been developed to protect RNA therapeutics from nuclease degradation and limit non-specific distribution in the body; yet significant challenges remain. The greatest failure of current vehicles is achieving effective targeted delivery of RNA therapeutics, thus, limiting RNA agents from exerting the desired therapeutic effect at the intended target site.

I develop approaches for rationally designing and engineering effective and stable targeted delivery systems and formulations for RNA therapeutics. During my PhD at the University of Cambridge, I put forth a novel strategy for rationally developing stable formulations, by characterising the structural dynamics of complex systems.¹ My research provided a deeper understanding of the key mechanisms of protein-excipient interactions which I demonstrated as a critical step in the rational development of stable protein formulation platforms. As a postdoctoral researcher of the Future Vaccine Manufacturing Research Hub, Imperial College London, I built on my knowledge and acquired a specialised skillset for strategically developing effective and stable delivery platforms for large-sized and negatively-charged RNA therapeutics. I have developed multiple strategies to overcome the limitations of existing commercial products. My more recent rational approaches for RNA-delivery system development, first require systematically accounting and defining the key biological barriers that the RNA-delivery system encounters and ought to overcome, from the point of administration to target-site arrival. Several of these obstacles include degradation, liver accumulation, cellular membrane transversal, internalisation and endosomal escape. Then, to overcome each of the defined barriers, RNA-delivery system design considerations are set-out, for example, carrier surface functionalisation, incorporation of targeting ligands and components eliciting stimuli-responsive release. Simultaneously, several design parameters, such as size and surface charge, of the carrier can be optimised, culminating in the construction of multifunction effective and stable RNA-delivery system formulations.

To date, implementing my rational design strategies has enabled (i) increasing the cellular uptake, transfection efficiency, and shelf life of self-amplifying RNA COVID-19 vaccines; (ii) improving the thermal stability of effective virus-like particles for distribution in low- and middle-income countries; (iii) the scalable manufacturing of stable polyethylene glycol (PEG) free LNPs, eliminating concerns related to the presence of anti-PEG antibodies; (iv) the formation of stable injectable hydrogels for localised delivery; (v) enhancing the targeted delivery of therapeutics across the blood-brain barrier in vivo.^2,3 Systematic experimental studies and molecular dynamic simulations revealed fundamental insight into the mechanisms of stabilisation and suppressed aggregation of protein therapeutics in strategically developed formulations.⁴ This along with my coined methods for predicting the thermodynamic parameters of protein therapeutics will be shown, which could advance designs of stable vaccine formulations. For my work, I have been awarded the Imperial College Research Fellowship. At present, I am simultaneously addressing multiple barriers in manufacturing, targeted delivery, stability, and storage by implementing several rational design strategies in the development of each formulation. Ultimately, I aim to sequentially address each of the identified barriers in pharmaceutical development and expand the design space, even providing solutions to challenges which we have yet to face.

Vision

I am equipped to lead a research group engineering the next generation of stable and effective targeted delivery systems and formulations for RNA therapeutics. My research interests include putting forth the guidelines for rationally designing and engineering (1) lipid and polymer-based nanocarriers, (2) hydrogels, (3) ionic liquid-based delivery systems, and (4) unmodified and chemically modified naked RNA (lacking a carrier) formulations. My expertise in rational design, the diverse mechanisms of action of delivery systems and large anionic RNA molecules will enable the rapid development of clinically relevant systems of industrial scale-up feasibility. My research will yield a multitude of translational avenues, and fundamentally deepen our understanding of the synergistic interactions within RNA-delivery system formulations, to realise the full potential of RNA therapeutics.

Teaching Interests

To date, I supported and directed the learning and research of BSc, MRes and PhD students. At the University of Cambridge, I delivered BSc small group tutorials and lab demonstrations in core bio- and chemical engineering courses and mentored a summer research exchange BSc student. For BSc students, I marked assignments, laboratory reports and entry examinations. I completed a teaching programme through the University of Cambridge Centre for Teaching and Learning and have been awarded an associate fellowship by the U.K. Higher Education Academy. At Imperial College London, I delivered chemistry seminars to BSc students, and to MRes students in the Institute for Molecular Science and Engineering I delivered a self-designed course on biopolymers for drug delivery systems. I have designed and guided thirteen interdisciplinary collaborative research projects for BSc, MRes and PhD students, was co-examiner on viva voce and marked MRes theses. The projects I conceived have attracted visiting students as well as Imperial College students. Given my background and experience, I will be particularly well placed to deliver content in bio- and chemical engineering, chemistry and materials science courses.

References

1. Shmool, T. A. Structural Dynamics of Amorphous Solid-State Macromolecular Materials at Terahertz Frequencies. PhD Thesis, University of Cambridge, United Kingdom, 2020.

2. Shmool, T. A.; Hallett, J. P.; Bhamra, A. K.; Chen, R. Stable Composition. PCT/GB2022/051392, WO 2022/254209.

3. Shmool, T. A.; Constantinou, A. P.; Jirkas, A. et al. Poly. Chem. 2022, 13, 2340-2350.

4. Shmool, T. A.; Martin, L. K.; Bui-Le, L. et al. Chem. Sci. 2021, 12, 9528-9545.