June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Recombinant Human MMP-3 Increases Outflow Facility In Vivo in Non-Human Primates and Ex Vivo in Human Cadaver Eyes
Author Affiliations & Notes
  • Jeffrey O'Callaghan
    Genetics, The University of Dublin Trinity College, Dublin, Ireland
  • Matthew Lawrence
    Virscio, Connecticut, United States
  • Merissa O'Connor
    Virscio, Connecticut, United States
  • Joseph Sherwood
    Bioengineering, Imperial College London, London, London, United Kingdom
  • Annahita Keravala
    Exhaura, Ireland
  • Christopher Stanley
    Virscio, Connecticut, United States
  • Thomas Walter Chalberg
    Exhaura, Ireland
  • Matthew Campbell
    Genetics, The University of Dublin Trinity College, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Jeffrey O'Callaghan Exhaura, Code C (Consultant/Contractor), Exhaura, Code P (Patent); Matthew Lawrence Exhaura, Code C (Consultant/Contractor), Virscio, Code O (Owner), Exhaura, Code P (Patent); Merissa O'Connor Virscio, Code E (Employment); Joseph Sherwood None; Annahita Keravala Exhaura, Code C (Consultant/Contractor), Exhaura, Code P (Patent); Christopher Stanley Exhaura, Code C (Consultant/Contractor), Virscio, Code O (Owner), Exhaura, Code P (Patent); Thomas Chalberg Exhaura, Code O (Owner), Exhaura, Code P (Patent); Matthew Campbell Exhaura, Code C (Consultant/Contractor), Exhaura, Code P (Patent)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2826 – A0342. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Jeffrey O'Callaghan, Matthew Lawrence, Merissa O'Connor, Joseph Sherwood, Annahita Keravala, Christopher Stanley, Thomas Walter Chalberg, Matthew Campbell; Recombinant Human MMP-3 Increases Outflow Facility In Vivo in Non-Human Primates and Ex Vivo in Human Cadaver Eyes. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2826 – A0342.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : We have previously reported that matrix metalloproteinase (MMP-3) increases outflow facility in wildtype mice. Here, we aimed to assess the translatability of MMP-3 in non-human primates (NHP) as well as human donor eyes (HDE) ex vivo.

Methods : Outflow facility was measured in vivo using a modified iPerfusion system. NHPs were anaesthetised with isoflurane, further stabilised by controlling body temperature and were monitored via electrocardiogram. Animals were intracamerally cannulated to iPerfusion, where 5 ng/ml recombinant human MMP-3 (rhMMP-3) was perfused into one eye for 1 hour at 5 mmHg above spontaneous IOP. An outflow reading was then taken while accounting for the time-dependent effect on outflow. Aqueous was sampled immediately after perfusion for ELISA analysis of MMP3 levels. To assess outflow in HDE, we designed eye baths and an incubator to extend the capabilities of the iPerfusion system. Anterior segments were mounted to baths, connected to iPerfusion and cultured for up to 2 weeks. Flow rates were stabilised before a baseline measurement was taken. The anterior chamber was then exchanged with 5 ng/ml rhMMP-3 using syringe pumps and another reading taken after 1 hour.

Results : Outflow facility was successfully measured in vivo in NHP eyes, with an average control facility of 0.45 /ul/min/mmHg. On average, outflow facility was significantly increased in non-human primates by 29 % (P = 0.006, n = 15) after exposure to rhMMP-3, with a moderate dose-response relationship observed (R2 = 0.46, P = 0.008). Heart rate and oxygen consumption were also related to facility using iPerfusion. In human donor anterior segments, outflow facility increased by 56 % on average after treatment (P = 0.14, n = 3 eyes).

Conclusions : Impaired outflow facility is a key driver of glaucoma pathophysiology, resulting in increased IOP and subsequent loss of glaucomatous degeneration. We successfully adapted the iPerfusion system for use with larger model systems. We have shown the translatability of therapeutic MMP-3-mediated increases in outflow in ex vivo mouse models, NHP in vivo, and post-mortem human donor eyes. Using MMP3 to increase conventional outflow holds promise as a potential new treatment for ocular hypertension and open angle glaucoma.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

×
×

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.

×