Human iPSC for Repair of Vasodegenerative Vessels in Diabetic Retinopathy

Vascular complications due to diabetes mellitus (DM) are the result of sustained vascular
injury with insufficient vascular repair. In chronic diabetes, vascular reparative mechanism
can be lost resulting in development of microvascular complications (MVC), such as diabetic
retinopathy (DR). We assessed the reparative function of progenitor cells that circulate in
the peripheral blood of diabetic individuals and found that the vascular wall-derived
progenitor cells, endothelial colony forming cells (ECFCs), were depleted in diabetics with
MVC. Bone marrow-derived progenitor cells, CD45+CD34+ were dysfunctional in diabetics with
MVC. We found that human inducible pluripotent stem cells (hiPSCs)-derived ECFCs displayed
the ability to form functional and durable blood vessels in vivo and conferred therapeutic
revascularization by connecting with and remaining integrated with host rodent vessels long
term. We characterized a mesoderm subset (SSEA5-KNA+ cells) generated from hiPSCs that gives
rise to ECFCs. Finally, we used hiPSCs to generate CD34+CD45+ cells and tested the impact of
co-administration of these cells with ECFCs within the vitreous. The addition of CD34+CD45+
cells with ECFCs resulted in the enhanced survival, function and reparative ability of the
ECFCs. This beneficial effect was mediated by reducing retinal oxidative stress and
inflammation.

These novel and paradigm shifting findings led us to hypothesize: the hiPSC-derived-mesoderm
subset (SSEA5-KNA+) can be utilized for long term revascularization of vasodegenerative
capillaries and their reparative action can be further enhanced by coinjection of CD34+CD45+
cells that provide anti-oxidant and anti-inflammatory effects.

Inclusion Criteria:

- Any man or woman between the ages of 21- 98 years of age will be eligible to
participate. To participate in the study as a study subject we will require: a) the
subject must either carry the diagnosis of diabetes or be a healthy aged control and
b) the patient be willing and have the ability to cooperate with the eye exam and skin
punch biopsy protocol.

Exclusion Criteria:

- We will apply the following exclusion criteria: a) evidence of ongoing acute or
chronic infection (HIV, Hepatitis B or C, tuberculosis); b) ongoing malignancy; c)
cerebral vascular accident or cerebral vascular procedure; d) current pregnancy; e)
history of organ transplantation; f) presence of a graft (to avoid any effect of the
graft on inflammatory parameters; and g) patients with anemia. Subjects with AMD,
glaucoma, uveitis, known hereditary degenerations or other significant ocular
complications other than diabetic retinopathy will be excluded.