(688b) Mathematical Modelling of Gene Delivery in Patients with Haemophilia B

Haemophilia B is a genetic bleeding disorder resulting from a deficiency of coagulation factor IX (FIX) caused by mutations in the gene that encodes FIX (George et al., 2017). Gene therapy is a potentially curative treatment option as it aims to restore, modify or enhance cellular functions through the introduction of therapeutic genes into target cells (Nathwani et al., 2011; 2014). However, optimising the dosing of therapeutic genes for patients remains a challenge, so detailed simulation of gene delivery systems is required for improved understanding of the system, leading to a model-based platform that can be used in clinical trial simulations to determine optimal dosing recommendations.

While a number of computational works provided insights into the process of gene delivery, there are several areas which are yet to be explored adequately. We have previously developed a model-based control algorithm for both efficacy and safety to provide quantitative understanding of non-viral siRNA delivery (Jamili and Dua, 2018). Having explored the nature and purpose of quantitative analysis of in vitro experimental data in our previous work, this study aims to develop a novel mathematical modelling approach, based on in vivo clinical data, for gene transfer of adeno-associated viral vectors in patients with haemophilia B.

The purpose of this work is to develop a modelling framework to predict the physiological response of a subject affected by type B haemophilia to a dose of vector. To address this, an integrated pharmacokinetic/pharmacodynamic (PK/PD) modelling platform was developed based on in vivo clinical data for three patients with severe haemophilia B whose functional plasma levels of FIX are less than 1% of the normal value. The plasma FIX activity was considered as the pharmacological effect while the level of serum alanine aminotransferase (ALT) demonstrated the hepatocellular toxicity. Both an individual-based modelling approach and a population modelling approach were used to estimate the physiological parameters of the developed PK/PD models. The models were then validated using data of the clinical study before being used in a simulation-based modelling approach to provide dosing recommendations. The results obtained in this study demonstrate a good prediction of the pharmacokinetics and pharmacodynamics of the vector. Model-based simulations were subsequently performed to guide initial dose selection in order to provide clinicians with better tools to make the decision-making process simpler for designing more effective treatment plans, which can be tailored to maximise efficacy while minimising toxicity for individual patients.

References

George, L. A., Sullivan, S. K., Giermasz, A., Rasko, J. E. J., Samelson-Jones, B. J., Ducore, J. et al. (2017) Hemophilia B gene therapy with a high-specific-activity factor IX variant. New England Journal of Medicine, 377(23), 2215-2227.

Jamili, E. & Dua, V. (2018) Optimal model-based control of non-viral siRNA delivery. Biotechnology and Bioengineering, 115(7), 1866-1877.

Nathwani, A. C., Reiss, U. M., Tuddenham, E. G. D., Rosales, C., Chowdary, P., McIntosh, J. et al. (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New England Journal of Medicine, 371(21), 1994-2004.

Nathwani, A. C., Tuddenham, E. G. D., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C. et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New England Journal of Medicine, 365(25), 2357-2365.