June 2020
Volume 61, Issue 7
ARVO Annual Meeting Abstract  |   June 2020
Gene therapy biofactory: Mathematical modeling of pharmacokinetics
Author Affiliations & Notes
  • Lucia Carichino
    School of Mathematical Sciences, Rochester Institute of Technology , Rochester, New York, United States
  • Giovanna Guidoboni
    Department of Electrical Engineering and Computer Science, Department of Mathematics, University of Missouri, Missouri, United States
  • Viral Kansara
    Clearside Biomedical Inc., Alpharetta, Georgia, United States
  • Thomas Ciulla
    Clearside Biomedical Inc., Alpharetta, Georgia, United States
  • Alon Harris
    Icahn School of Medicine, Mount Sinai, New York, United States
  • Footnotes
    Commercial Relationships   Lucia Carichino, None; Giovanna Guidoboni, Foresite Healthcare LLC (C), Gspace LLC (I); Viral Kansara, Clearside Biomedical Inc. (E), Clearside Biomedical Inc. (I); Thomas Ciulla, Clearside Biomedical Inc. (E), Clearside Biomedical Inc. (I); Alon Harris, AdOM (C), AdOM (I), AdOM (S), AdOM (R), LuSeed (I), Oxymap (I), Thea (R)
  • Footnotes
    Support  NSF DMS-1853222/1853303
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2872. doi:
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      Lucia Carichino, Giovanna Guidoboni, Viral Kansara, Thomas Ciulla, Alon Harris; Gene therapy biofactory: Mathematical modeling of pharmacokinetics. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2872.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Gene therapy can be utilized in a “biofactory approach” to produce non-native proteins, as is already being assessed for the treatment of inherited retinal disease, neovascular retinal disease, and uveitis. In neovascular age related macular degeneration (nAMD), gene therapy is explored to chronically express anti-vascular endothelial growth factor (anti-VEGF) proteins and relieve treatment burden of current therapy. Aqueous humor levels (AHLs) of anti-VEGF protein can be measured in the clinical setting, unlike in other ocular compartments. Here, a theoretical model is used to predict anti-VEGF retina and vitreous levels (RLs and VLs), and the retina anti-VEGF production rate (r) using this biofactory approach.

Methods : A model of ocular pharmacokinetics in three ocular compartments (aqueous, vitreous and retina) is used to describe the anti-VEGF levels in the eye. The model dynamics is driven by the outflow and intra-compartment transport pathways, and by r in the retina. The model geometrical parameters are scaled from rabbit to human eyes following Hutton-Smith et al. 2017 and Missel 2012. Using publicly disclosed information of AHLs from a current nAMD gene therapy trial (NCT03066258), the model is used to predict the corresponding RLs, VLs, and r.

Results : The model results are obtained for five AHLs: 2.5, 12.8, 160.2, 249.4 and 376.0 ng/ml. Results suggest that AHLs>160ng/ml correspond to RLs between 4x103 and 11x103 ng/ml, while AHLs<160ng/ml correspond to RLs<0.4x103 ng/ml, see Figure 1. Moreover, the model predicts that an AHL increase of 10 ng/ml corresponds to a VL increase of 45.2 ng/ml, a RL increase of 291.4 ng/ml, and it is due to an increase of 469.5 ng/ml/day in r.

Conclusions : The model allowed to estimate the therapeutic protein levels in the retina and vitreous, and shows an AHL-dependent increase of these levels. Future studies are needed to expand the model to account for the retina pigmented epithelium and choroid compartments, that contribute to the production of the anti-VEGF protein in this biofactory approach, and whose levels are challenging to extract in the clinical setting. In the future, precision medicine aided by mathematical modeling could be employed after anterior chamber diagnostic testing of pathologic proteins, to select therapeutic options of different gene therapy biofactory approaches.

This is a 2020 ARVO Annual Meeting abstract.


Figure 1: Model results

Figure 1: Model results


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