Optimizing systemic stem/progenitor cell therapy for AMD

  • Boulton, Michael (PI)

Project: Research project

Project Details


Age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly.
Despite knowledge of the cell types involved, therapeutic intervention has been limited and there is
currently no treatment for nonexudative AMD. While RPE cell transplantation into the subretinal
space of patients offered a promising therapeutic approach, outcomes to date have been limited
due to: 1) transplantation in late stage disease, 2) the invasive route of administration, and 3)
incomplete differentiation status of the transplanted cells. To address these limitations, we have
made a number of exciting discoveries: 1) forced expression of the RPE65 gene allows mouse
hematopoietic stem cells (mHSC), when injected back into the circulation, to home to the retina and
renew the RPE monolayer in both acute and chronic mouse models of RPE loss and re-establish
visual function; 2) the circadian pattern to endogenous HSC release impacts reconstitution
following bone marrow transplantation; 3) microglial activation in AMD will require modulation to
ensure efficient RPE regeneration by HSCs; 4) a highly effective non-viral protein delivery
machinery (T3SS) is able to deliver target proteins into host HSCs and promote their differentiation;
5) human hematopoietic progenitor cells (hHPCs), when programmed with RPE65, express RPE
cell markers. Based on these observations we hypothesize that: Successful therapeutic
utilization of human or murine HSC requires their programming prior to injection into the
systemic circulation, their injection at the time of optimal engraftment potential and
preconditioning of the retina by either suppression of resident microglia activation and/or
restoring the balance of peripheral pro-inflammatory and homeostatic monocytes. The
hypothesis is addressed in three Aims. In Aim 1 we will determine the dependence of recruitment
and incorporation of programmed mHSC into the injured RPE in the SOD2 KD mouse model upon
the time of day of injection and the age of the donor HSC as well as the age of the recipient. Aim 2
will investigate the importance of manipulating the retinal environment, by controlling either the
activation state of the resident microglia or the influx of peripheral monocytes on the efficiency of
systemically administered programmed mHSC to repair the RPE layer in the SOD2 KD model. Aim
3 will translate our mouse findings into hHPCs. We will express RPE65, in human CD133+, CD 34-
, CD38- cells to differentiate these cells toward RPE cells and allow RPE regeneration in SCID
mice undergoing the SOD2 KD model. Co-injection of mesenchymal stem cells will be utilized to
reduce activation of resident microglia. Our approach overcomes many of the current limitations of
human stem cell therapies for AMD.
Effective start/end date9/30/138/31/18


  • National Institutes of Health: $589,587.00
  • National Institutes of Health: $513,987.00
  • National Institutes of Health: $515,942.00


  • Medicine(all)


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