June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Targeted intravenous dendrimer-drug therapies for AMD
Author Affiliations & Notes
  • Kannan Rangaramanujam
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Siva Pramodh Pramodh Kambhampati
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Imran Ahmed Bhutto
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Tony Wu
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Scott McLeod
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Gerard A Lutty
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Kannan Rangaramanujam, Ashvattha Therapeutics LLC (C), Johns Hopkins University (P); Siva Pramodh Kambhampati, Johns Hopkins University (P); Imran Bhutto, None; Tony Wu, None; Scott McLeod, None; Gerard Lutty, Johns Hopkins University (P)
  • Footnotes
    Support  National Eye Institute NEI-R01EY025304
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4929. doi:
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      Kannan Rangaramanujam, Siva Pramodh Pramodh Kambhampati, Imran Ahmed Bhutto, Tony Wu, Scott McLeod, Gerard A Lutty; Targeted intravenous dendrimer-drug therapies for AMD. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4929.

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

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Abstract

Purpose : AMD is a multifactorial disease in which inflammation and oxidative stress play a key role early with neovascularization manifested in later stages. Current intravitreal anti-VEGF therapies for wet AMD only neutralize extracellular VEGF but does not address inflammation or intracellular VEGF. We showed that intravenously administered PAMAM dendrimer-drug conjugates selectively target activated microglia/macrophages (mi/ma) and hypertrophic RPE. The purpose of this study was to evaluate the efficacy of intravenously injected PAMAM dendrimers drug conjugates in a lipid-induced rat AMD model.

Methods : Dendrimer-triamcinolone acetonide (D-TA) and Dendrimer-N-acetyl cysteine (D-NAC) conjugates were synthesized using scale-up amenable protocols. Cy5-labelled conjugates were used to evaluate biodistribution. For early AMD, monotherapy of D-NAC or D-TA was administered intravenously on day 3, 5 and 7 post lipid injection and assessed on day 10. For late AMD, combination therapy with D-NAC+D-TA was administered intravenously on day 10, 12 and 14 post lipid injection and accessed on day 21. Retinas and choroids were prepared for flat-mount and cross-section IHC and imaged under confocal microscope for CNV area, volume and macrophage counts. Attenuation of inflammation was assessed using RT-qPCR for cytokines expression.

Results : Subretinal lipid demonstrated pathological events similar to that of human AMD. Monotherapy with either D-TA or D-NAC resulted in significant suppression of CNV formation (>75%), reduction in mi/ma in the CNV areas (>60%) and attenuated inflammation by suppressing inflammatory cytokines, oxidative stress makers and VEGF. Combination (D-NAC+D-TA) therapy promoted CNV regression (~72%) with reduced CNV volume, enhanced anti-inflammatory and adhesion molecule expression with reduced leakage in late AMD compared to free drug controls with no signs of systemic toxicity. Further, ex vivo uptake studies in diabetic human donor eyes, dendrimers were taken up by choroidal macrophages demonstrates the platform may target these cells even in humans.

Conclusions : The results suggest that systemic dendrimer-drug therapy demonstrates efficacy in attenuating CNV and inflammation, addressing intracellular VEGF, without exposing the eye to high drug concentrations. The positive results in CNV suppression/regression offer new avenues for therapies for both early/late AMD and many other posterior segment diseases.

This is a 2020 ARVO Annual Meeting abstract.

 

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