July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Extended preclinical ocular biodistribution and pharmacodynamic profile of ISTH0036, an antisense oligonucleotide targeting transforming growth factor beta 2 (TGF-β2) for the treatment of ophthalmic diseases
Author Affiliations & Notes
  • Katja Wosikowski
    Preclinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Birgit Korbmacher
    Covance Preclinical Services GmbH, Münster, Germany
  • Monika Krampert
    LGC AxoLabs, Kulmbach, Germany
  • Ingo Roehl
    LGC AxoLabs, Kulmbach, Germany
  • Michel Janicot
    Preclinical Research and Development, Isarna Therapeutics, Munich, Germany
  • Footnotes
    Commercial Relationships   Katja Wosikowski, Isarna Therapeutics (C), Isarna Therapeutics (P); Birgit Korbmacher, Covance Preclinical Services (E); Monika Krampert, LGC AxoLabs (E); Ingo Roehl, LGC AxoLabs (E); Michel Janicot, Isarna Therapeutics (C), Isarna Therapeutics (P)
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5702. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Katja Wosikowski, Birgit Korbmacher, Monika Krampert, Ingo Roehl, Michel Janicot; Extended preclinical ocular biodistribution and pharmacodynamic profile of ISTH0036, an antisense oligonucleotide targeting transforming growth factor beta 2 (TGF-β2) for the treatment of ophthalmic diseases. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5702.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : A critical role for TGF-β2 in the pathophysiology of several ocular diseases such as glaucoma, age-related macular degeneration or diabetic macular degeneration has been demonstrated, making this cytokine a relevant therapeutic target. To support clinical development in these indications, the ocular biodistribution and pharmacodynamics profile of ISTH0036, a 14-mer phosphorothiate locked nucleic acid-modified antisense oligodeoxynucleotide gapmer, was evaluated in Cynomolgus monkeys following intravitreal administration.

Methods : To assess the time-dependency of ocular tissue drug biodistribution and pharmacodynamics effects, ISTH0036 was administered on Day 1 and Day 57 at a dose of 100 µg/eye to Cynomolgus monkey eyes. Furthermore, single administrations of the compound at increasing doses of 30, 100 and 300 µg/eye were performed to assess the dose-dependency on Day 29. An anion-exchange-HPLC method with fluorescence detection was used to analyze tissue concentrations. Target downregulation was determined using a branched DNA assay, protein concentration in humors with a multiplex ELISA assay.

Results : Long-lasting and time-dependent biodistribution of ISTH0036 to the posterior eye tissues was observed. Similar high ISTH0036 concentrations were measured in the retina, choroid and ciliary body after 300 µg/eye administration (on Day 29: 5-6 µg/g). High median drug concentrations in posterior eye tissues were still observed on the last day of measurement (Day 113). ISTH0036 induced in vivo long-lasting and dose-dependent TGF-β2 mRNA downregulation in retina and lens. TGF-β2 protein concentration decreased in the vitreous humor after intravitreal injection of ISTH0036 and this effect was long-lasting, up to Day 113. These results confirm previous findings in the rabbit eye.

Conclusions : ISTH0036 demonstrated potent target TGF-β2 mRNA downregulation in relevant tissues of the Cynomolgus monkey eye. Long-lasting posterior eye tissue distribution was consistent with the observed target engagement. Demonstrated biodistribution and target engagement supports further clinical development and provides rationales for Q2M or Q3M administration schedules of ISTH0036 in the ophthalmic setting.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×