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Matrix metalloproteinase-3 (MMP-3)-mediated gene therapy for glaucoma.

Jeffrey O'Callaghan1, Conor Delaney1, Merissa O'Connor2

  • 1Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.

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|April 19, 2023
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Gene therapy using adeno-associated virus 9 (AAV9) to deliver matrix metalloproteinase-3 (MMP-3) effectively increased ocular fluid outflow in animal models and human eyes, offering a promising new glaucoma treatment.

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Area of Science:

  • Ophthalmology
  • Gene Therapy
  • Biochemistry

Background:

  • Glaucoma affects 80 million globally, projected to exceed 110 million by 2040.
  • Topical eye drops face compliance issues and treatment resistance, risking vision loss.
  • Elevated intraocular pressure, a key glaucoma risk factor, is linked to aqueous humor outflow resistance.

Purpose of the Study:

  • To investigate the efficacy of AAV9-mediated MMP-3 gene therapy for enhancing aqueous humor outflow.
  • To assess the safety and tolerability of long-term AAV9 transduction in nonhuman primate corneal endothelium.
  • To determine the effect of MMP-3 on outflow in donor human eyes.

Main Methods:

  • Adeno-associated virus 9 (AAV9) vector delivery of matrix metalloproteinase-3 (MMP-3) gene.
  • In vivo studies in murine glaucoma models and nonhuman primates.
  • Ex vivo studies using donor human eyes.

Main Results:

  • AAV9-MMP-3 gene therapy significantly increased ocular outflow in murine models and nonhuman primates.
  • Long-term AAV9 transduction of corneal endothelium in nonhuman primates proved safe and well-tolerated.
  • MMP-3 demonstrated increased outflow in donor human eyes.

Conclusions:

  • AAV9-mediated MMP-3 gene therapy represents a viable strategy for treating glaucoma by improving aqueous humor outflow.
  • This gene therapy approach shows potential for clinical translation, offering a novel treatment for glaucoma patients.
  • The safety and efficacy observed in preclinical models suggest a promising path toward clinical trials for glaucoma gene therapy.