July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Potential cancer therapy for activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection
Author Affiliations & Notes
  • Thomas Wubben
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Mercy D Pawar
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Eric Weh
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Zuzanna Lutrzykowska
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Andrew Smith
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Cagri G Besirli
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Thomas Wubben, University of Michgan (P); Mercy Pawar, None; Eric Weh, None; Zuzanna Lutrzykowska, None; Andrew Smith, None; Cagri Besirli, University of Michgan (P)
  • Footnotes
    Support  VitreoRetinal Surgery Foundation Research Award
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5178. doi:
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      Thomas Wubben, Mercy D Pawar, Eric Weh, Zuzanna Lutrzykowska, Andrew Smith, Cagri G Besirli; Potential cancer therapy for activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5178.

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

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Abstract

Purpose : Photoreceptor (PR) death is the root cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve PR survival. We recently demonstrated that genetically reprogramming PR metabolism via pyruvate kinase muscle isozyme 2 (PKM2)-to-PKM1 substitution is a novel neuroprotective strategy. As such, we sought to assess the PR neuroprotective effects of pharmacologically activating PKM2 via ML-265, a potential cancer therapy, during acute outer retinal stress.

Methods : The effect of ML-265 on pyruvate kinase (PK) activity was determined with recombinant PKM2 as well as in vitro in the 661W cone-like PR cell line, and in vivo via intravitreal injections into rat eyes. Single-dose, intravitreal injection, pharmacokinetic studies were performed in rabbits. The long-term effects of treatment on the rat retina were examined with OCT and ERG. RT-PCR analyzed changes in glucose metabolism gene expression. Apoptosis was induced in 661W cells with a Fas-activating antibody (FasL), and outer retinal stress was induced via experimental retinal detachment in rats in the presence of ML-265 or vehicle. Caspase activities and cell viability were assessed in cell lysates and retinal extracts.

Results : Pharmacological activation of PKM2 with ML-265 increased PK activity in all assays upwards of 200% with AC50 measurements in the nanomolar range. The in vivo half-life of ML-265 after intravitreal injection was 177 hours. No differences in scotopic or photopic ERG amplitudes or in vivo retinal thickness measurements were observed between ML-265 and vehicle-treated eyes after 6 weekly, intravitreal injections in rats. No significant changes in glucose metabolism gene expression were observed between ML-265 and vehicle in vitro or in vivo. Importantly, ML-265 treatment significantly decreased Fas-induced caspase activation and improved viability in 661W cells, and reduced entrance into the apoptosis cascade as seen by decreased caspase activity after experimental retinal detachment.

Conclusions : This study shows that pharmacologic activation of PKM2 via the small molecule, ML-265, decreases PR apoptosis during outer retinal stress and provides evidence that reprogramming metabolism via activation of this key glycolytic regulatory enzyme is a novel, PR neuroprotective strategy that may be translatable to many retinal disorders.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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