Vivek Dua
University College London
Objectives: Obtain optimal cellular exposure and transfection by formulating and solving a constrained multi-objective optimal control problem to compute the optimal dosage injection rate in the presence of constraints on the injection rate and cytotoxicity.
Methods: Gene therapy can potentially become a viable tool for the effective treatment of diseases. For effective gene therapy a gene delivery system has to balance between the two main objectives: high efficacy and low toxicity. However, usually these two objectives conflict with each other, i.e. one objective can not be improved without sacrificing the other. Several mathematical models have emerged recently to quantify the rates of transfer across various biological barriers. These models are based upon in vitro experiments where plasmid concentration in the medium at the start of the experiment is given and no additional plasmid is added to the medium during the experiment. For in vivo applications, the initial plasmid concentration can be initially zero and then plasmid is infused over a period of time. To take infusion into account we have modified the model and then use it to ask the question – what is the optimal gene delivery rate?
Polymeric carriers can assist delivery of genetic material to cross various biological barriers including cell membrane binding, endocytosis, endosomal escape, and nuclear entry. Some high molecular weight polymeric carriers have high transfection efficiency but are also highly cytotoxic. To manifest the desired therapeutic effect, optimal cellular exposure and transfection must be achieved. In this work, optimal cellular exposure and transfection are obtained by formulating and solving a constrained optimal control problem to compute the optimal dosage injection rate in the presence of constraints on the injection rate and cytotoxicity.
Results and Conclusions: The proposed gene delivery optimal control problem (GENOCT) problem explicitly takes into account the dynamic model of the transport across the biological barriers. The solution of the GENOCT problem provided some very interesting insights on what gene delivery profile might look like in a clinical setting and also on how these profiles are affected by the trade-offs between efficacy and toxicity.
Reference: PAGE 21 () Abstr 2424 [www.page-meeting.org/?abstract=2424]
Poster: New Modelling Approaches