Senior Modeler Rosa & Co. LLC Estepona, Andalucia, Spain
Disclosure(s):
Alvaro Ruiz-Martinez, PhD: No financial relationships to disclose
Objectives: A challenge in designing human gene therapy trials is dose selection, given that the translation of dose from animals to humans is not easily predictable. Recently, quantitative system pharmacology (QSP) approaches have been used to better understand the mechanisms that impact gene therapy distributions to tissues of interest and gene transduction efficiencies. Here, we present a PBPK-QSP model capable of representing the biodistribution of any Adeno-associated virus (AAV) or Lipid Nanoparticle (LNP) vector administered by varied routes. As a first case study toward this goal, the model was developed to represent the biodistribution and transduction efficiency of a mock payload delivered by AAV-2 administered by intravenous injection in mouse, non-human primate (NHP), and human.
Methods: The model includes a plasma compartment and four generic tissue compartments that share an identical structure, representing target-tissues (eye, brain, muscle) and pooled non-target tissues, for the vector-delivered transgene. These compartments are all independent from each other and connected through the plasma. Each compartment includes an interstitial space and cellular representation consisting of membrane, cytoplasm, and nucleus. Cellular attachment, internalization, nuclear transport, uncoating, and transgene production are represented. Pre-clinical and literature data were used to create and calibrate a virtual mouse and a virtual NHP and to define the dependence of parameters on variables such as species, tissue, vector, or payload. Additionally, a virtual human was developed and tested qualitatively using literature data to define extracellular parameters and assuming similar intracellular parameters across species.
Results: A virtual mouse was created that quantitatively captured the biodistribution of AAV-2 at 2 min and 2 weeks post-administration as reported in a case study [1]. Similarly, a virtual NHP matched the biodistribution of AAV-2 at 3 months post-administration as reported in [2]. In both cases, the model was able to capture the sum of the extracellular amount of vector genome per mass of DNA in tissue, i.e., the sum of AAV in the vasculature, tissue, membrane, and cytoplasm, as well as AAV and double-stranded DNA in the nucleus. The virtual human simulations showed the model’s ability to predict both AAV and protein levels and capture the effects of neutralizing antibodies on the efficacy of the treatment.
Conclusions: A gene therapy PBPK-QSP model was developed to enable species translation of a gene therapy biodistribution and transduction. The model has the flexibility of capturing the delivery of gene therapies using either AAV or LNP vectors to target tissues of interest by varied administration routes. Target tissues and their associated payloads delivered by the given vector can also be selected for representation as needed. Parameters within the model can be modified to reflect these differences, rendering the model a versatile research tool.
Citations: [1] J. Korbelin et al. Mol Ther (2016) 24 (6):1050-1061. [2] S. Mori et al. Jpn J Infect Dis (2006) 59 (5):285-93.
