July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Combining ISTH0036, an antisense oligonucleotide targeting Transforming Growth Factor beta 2 (TGF-β2) mRNA, with aflibercept as novel treatment strategy for neovascular retinal diseases
Author Affiliations & Notes
  • Michel Janicot
    Preclinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Giedrius Kalesnykas
    Experimentica Ltd, Kuopio, Finland
  • Eugen Leo
    Clinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Petra Fettes
    Clinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Simon Kaja
    Experimentica Ltd, Kuopio, Finland
  • Katja Wosikowski
    Preclinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Footnotes
    Commercial Relationships   Michel Janicot, Isarna Therapeutics (C), Isarna Therapeutics (P); Giedrius Kalesnykas, Experimentica (E); Eugen Leo, Isarna Therapeutics (C), Isarna Therapeutics (P); Petra Fettes, Isarna Therapeutics (E), Isarna Therapeutics (P); Simon Kaja, Experimentica (E); Katja Wosikowski, Isarna Therapeutics (C), Isarna Therapeutics (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 236. doi:https://doi.org/
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      Michel Janicot, Giedrius Kalesnykas, Eugen Leo, Petra Fettes, Simon Kaja, Katja Wosikowski; Combining ISTH0036, an antisense oligonucleotide targeting Transforming Growth Factor beta 2 (TGF-β2) mRNA, with aflibercept as novel treatment strategy for neovascular retinal diseases. Invest. Ophthalmol. Vis. Sci. 2018;59(9):236. doi: https://doi.org/.

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

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Abstract

Purpose : Anti-VEGF agents represent the current main option for treatment of neovascular eye diseases. However, suboptimal response and emerging resistance represent a significant clinical challenge. ISTH0036 is a 14-mer phosphorothiate locked nucleic acid-modified antisense oligonucleotide targeting TGF-β2 mRNA, and was shown to have potent anti-vascular leakage, anti-angiogenic and anti-fibrotic effects in prior studies. In line with the function of its target, also a blockade of epithelial-to-mesenchymal transition is suspected for ISTH0036, a process involved in RPE cell alteration during choroidal neovascularization (CNV). The aim of the presented studies was to evaluate a possibly beneficial therapeutic potential of this combination in a murine model of laser-induced CNV following intravitreal (IVT) administration

Methods : The effect of ISTH0036 was studied in a murine CNV model by performing 3 laser-induced burns on the Bruch’s membrane of C57Bl/6JR mouse eyes. ISTH0036 and aflibercept were IVT administered immediately after CNV induction. The mice were followed for 14 days using in vivo imaging (fluorescein angiography and spectral domain optical coherence tomography).

Results : Mice treated with ISTH0036, aflibercept or with a combination of aflibercept and ISTH0036 had a significantly lower percentage of CNV lesions as compared to the vehicle group when measured between day 5 and day 14, with ISTH0036 having similar potency as aflibercept. The lowest percentage of CNV lesions on day 5 and day 14 was found in the group treated with a combination of aflibercept and ISTH0036. As additional, alternative approach, CNV lesions were re-graded based on the presence of “no” or “small” vascular leakage (grade 1) as observed on Day 14. While the vehicle group showed the lowest number of grade 1 lesions, the combination group had the highest number of grade 1 lesions, showing the most favorable shift away from higher-grade lesions.

Conclusions : Combining aflibercept with ISTH0036 resulted in significantly reduced CNV induction and severity in this mouse model. In head-to-head comparisons ISTH0036 was equipotent to aflibercept. ISTH0036 may with its novel mode of action and preclinical potency represent a promising new combination treatment strategy with aflibercept. Clinical evaluation of this approach is in planning.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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