Oral Presentation Australia and New Zealand Society for Extracellular Vesicles Conference 2023

Local administration of extracellular vesicles from bone marrow-derived mesenchymal stem cells restores homeostatic communication pathways and slows the progression of retinal degeneration (#21)

Nathan J Reynolds 1 2 , Yvette Wooff 1 , Adrian Cioanca 1 , Mitch Shambrook 3 , Xenia Sango 4 , Smriti Krishna 4 , David Haylock 4 , Riccardo Natoli 1 2
  1. John Curtin School of Medical Research, The Australian National University, Canberra
  2. School of Medicine and Psychology, The Australian National University, Canberra
  3. La Trobe University, Melbourne
  4. VivaZome Therapeutics, Melbourne

Aims

Age-related macular degeneration (AMD) is a neurodegenerative disease characterised by irreversible vision loss. In the degenerating retina, we have previously shown that a loss of extracellular vesicle (EV) bioavailability is correlated with key pathological features of AMD including photoreceptor cell death and large-scale inflammatory cascades. We therefore hypothesise that replenishment of EV from cells shown previously to have therapeutic benefits to the eye, such as bone marrow-derived mesenchymal stem cell EV (BM-MSC-EV), and their molecular cargo, may restore lost EV homeostatic communication pathways, slowing the progression of degeneration.

Methods

EV were isolated from BM-MSC cell culture supernatant using tangential flow filtration and size exclusion chromatography. EV or vehicle (PBS) were administered to the retina via intravitreal injection at a dose of 2.0x109 EV/μL (1μL) prior to degeneration using a well-established photo-oxidative damage model of retinal degeneration (100k lux bright white-light for 5 days). Electroretinography and optical coherence tomography were used to measure retinal function and morphology respectively following degeneration, while TUNEL and IBA-1+ immunohistochemistry was conducted on retinal cryosections to determine levels of cell death and inflammation.

Results

Compared to PBS-injected controls, delivery of BM-MSC EVs resulted in significantly higher retinal function, reduced presence of infiltration and activated microglia/macrophages as a measure of inflammation, and decreased levels of retinal cell death.

Conclusions

Our data supports BM-MSC-EV as a potential therapeutic EV source to slow the progression of retinal degeneration. These data suggest BM-MSC may provide a novel EV source for delivery of current and future therapeutics for retinal degeneration.

  1. Wooff, Y. et al. Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy. Frontiers in Cellular Neuroscience 14, doi:10.3389/fncel.2020.00160 (2020).
  2. Mead, B., Amaral, J. & Tomarev, S. Mesenchymal Stem Cell–Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Investigative Ophthalmology & Visual Science 59, 702-714, doi:10.1167/iovs.17-22855 (2018).