Health Sciences PhD student awarded Google Fellowship

PhD student Dennis Dogbey, from the Medical Biotechnology and Immunotherapy (MB&I) Research Unit at the University of Cape Town’s (UCT) Institute of Infectious Disease and Molecular Medicine based at the Faculty of Health Scienceswas recently awarded a 2021 Africa PhD Google Fellowship for Human-Computer Interactions – as this year’s only African recipient in this subfield.

Viral vectors are molecular tools used by scientists to deliver genetic material into cells. They have been used successfully for the treatment of many hereditary diseases and show great promise for the development of future anti-cancer therapies. Though about four viral vector-based gene therapies have been approved for use in patients, with several hundred currently being tested in clinical trials, various technological hurdles must be overcome to realise the full extent of their clinical impact.

One of the main bottlenecks with the use of viral vectors, especially in the context of cancer gene therapy, is how to selectively deliver these vectors into target tissue and organs in the body. Due to their relatively small size and natural ability to transfer genetic material between cells in more than one tissue, the targeted systemic delivery of viral vectors to distant organs is currently impossible.

“Our aim is to integrate commonly used viral vectors to develop a targeted drug-delivery system, based on a knowledge-driven and innovative approach.”

In Dogbey’s project, the surface of viral vectors will be decorated with disease-specific antibodies using state-of-the-art computational and protein engineering methods. This novel approach will allow selective delivery of viral vectors to identified diseased cell populations. When used for cancer gene therapy, these viral vectors will allow the targeted delivery of toxic anti-cancer genes into tumour cells without harming normal cells.

Dogbey explained: “Certain cancer types continue to be a significant burden – especially in Africa, where treatment is done through conventional strategies like chemotherapy, surgery, and radiation therapy. These often cause severe negative effects and can make the patient resistant to the treatment.

“Our aim is to integrate commonly used viral vectors to develop a targeted drug-delivery system, based on a knowledge-driven and innovative approach.”

MB&I opening a new line of research

The Google Fellowship is offered in Africa, Australia, Canada, East Asia, Europe, India, New Zealand, South-east Asia and the United States. Five other fellowships were awarded in Africa under different subfields.

According to the fellowship mandate, the award is designed to directly support graduate students as they pursue their PhDs, as well as to connect them to a Google Research Mentor to nurture and maintain strong relations with the academic community. The fellowship was created to recognise exceptional graduate students conducting cutting-edge and innovative research in areas relevant to computer science and related fields, who also hold an ambition to influence the future of technology.

“This Google fellowship is the type of desperately needed support highlighting the power of interdisciplinary collaborations.”

“This Google fellowship is the type of desperately needed support highlighting the power of interdisciplinary collaborations between computer simulation and applied research, especially in the area of knowledge-driven innovation in medical biotechnology,” said Professor Stefan Barth, who established the MB&I Research Unit.

“This kind of appreciation is allowing us to expand our activities into two main areas of research exemplified by a) using supercomputer simulation of dynamic protein interactions to design next generation recombinant immunotherapeutics, as illustrated in Designing the sniper: improving targeted human cytolytic fusion proteins for anti-cancer therapy via molecular simulation a paper resulting from a collaboration between Professor Barth and Professor Paolo Carloni, the director at the Institute for Advanced Simulation, FZ Jülich Germany, and (b) using bioinformatics big-data interpretation tools to identify disease-specific biomarkers for precision, medicine-driven immunodiagnosis and therapy,” added Professor Barth, who was awarded a Tier 1 South African Research Chair in Cancer Biotechnology in 2015, which subsequently became an integral part of UCT’s Department of Integrative Biomedical Science. Barth has 25 years of experience in recombinant antibody technologies and knowledge-based innovation creation in the field of medical biotechnology.

He added: “This is opening a new line of research, where we are using the background knowledge accumulated on antibody engineering to contribute to targeted gene therapy approaches. The future impact is strongly dependent on a successful proof-of-concept of Dennis’ practical work.”

Going forward, the main goal of the fellowship is to intensify the work Dogbey is doing at the lab.

Innovations to improve gene therapy

MB&I aims to provide the best possible scientific content and working environment in a resource-limited setting – which is the case in Africa. The quality of research produced by the research unit is documented by the theses of student graduates. This provides a strong basis for the continuation of this research work, by contributing to innovative protein engineering to deliver next-generation diagnostics and therapeutics.

“After several years of work, we have since demonstrated early proof-of-concept studies for our recombinant antibody approaches.”

Referring to the role of the research unit’s work, Dogbey said: “The MB&I is known for its knowledge-driven innovative research outputs – some of which have been granted international patents. It was a case of ideas meeting ideas. As far back as 2016, Dr Olusiji Alex Akinrinmade – then a PhD student, under Prof Barth – began working on targeted viral vectors. Aside from these, ongoing studies from advanced countries attempted the development of targeted viral vectors to improve gene therapy. A few publications from technologically advanced countries attest to this.”

Dr Akinrinmade, postdoctoral fellow at MB&I, said that when he was admitted as the first PhD student by Barth, he was encouraged to establish the targeted delivery of viral vectors using the platform technologies available at the research unit. “After several years of work, we have since demonstrated early proof-of-concept studies for our recombinant antibody approaches. We now possess the technical know-how needed to achieve our primary aims.”

Confident that results from this work will significantly contribute to healthcare by meeting an unmet medical need in the field of gene therapy, Akinrinmade explained: “Currently, there is no platform technology available in clinics for the targeted delivery of therapeutic genes to specific organs in the body. The results from this project will provide stakeholders with the technical know-how for preparing next-generation targeted gene delivery cargoes.”

According to Dogbey, this line of research is particularly challenging because of several shortfalls that are associated with the modification of most viral vectors. For example, previous work has shown that the biology of most viral vectors can easily be compromised by the insertion of foreign structural sequences into the viral genome. In other instances, modification of viral vectors with antibodies can result in very low viral titres (yields) during production, resulting in insufficient quantities for preclinical or clinical testing.

“The deliverables from this project will include a portfolio of antibody-based targeted gene delivery vectors engineered to make an impact in the cancer gene therapy landscape,” said Dogbey.