Accelerated Repair of Vascular Injury in Diabetic Retinopathy by Autologous TGF-β-Modified Hematopoietic Stem Cells

Funding Type: 
Early Translational I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

We propose to develop an efficient, safe clinical treatment for diabetic retinopathy using human adult stem cells that have been activated to repair damaged vessels in the eye. Despite advances in our understanding of how diabetic retinopathy occurs, no effective treatment exists to reverse the retinal blood vessel damage and the vision loss resulting from lack of blood/oxygen supply to the retina. Diabetic retinopathy remains the leading cause of irreversible blindness among working-age adults despite the use of laser and drug therapy, and retinal surgery to treat complications of diabetic retinopathy such as swelling of the retina, bleeding in the eye or retinal detachment. Adult blood and bone marrow contain stem cells that can repair damaged tissue and blood vessels. In disease these stems cells have limited repair capability and chronic diabetes further severely disrupts the ability of these stem cells to repair damaged blood vessels.

We have shown that these adult stem cells treated temporarily with a drug that blocks an important regulator of stem cell inactivation (i.e. , transforming growth factor-beta, TGF-β) greatly enhances vessel repair capability of these stem cells, and importantly stem cells from diabetic patients, as well. Thus, this stem cell activating drug may allow diabetic patients to use their own stem cells to treat their diabetic retinopathy. Using a patient's own stem cells is much safer and potentially more effective since rejection is not an issue.

In this proposal, we plan to determine the best source of the stem cells. We will compare the repair capacity of adult stem cells obtained from blood and the bone marrow since there is data to suggest that bone marrow derived adult stem cells may repair better than stem cells from blood vessels. We will also compare the repair capacity of the stem cells obtained from diabetic patients to that from non-diabetic patients since preliminary data suggest that stem cells from bone marrow of non-diabetic normal donors may repair better than stem cells from peripheral blood. We will then compare the effect of blocking TGF-β on these stem cells from different sources in order to determine the best source of stem cells for treating diabetic retinopathy.

Next, we want to determine whether these adult stem cells work better when they are injected directly into the eye versus injected into the blood stream. Injecting directly into the eye is simpler and safer but since diabetes is a systemic disease, systemic administration may be more effective. We also will determine if either route of stem cell therapy is safe and effective in the long-run.

Once we complete the proposed studies, we will be able to plan a clinical trial to treat patients with diabetic retinopathy using their own stem cells. If this treatment proves to be effective, it will be the first “cure” for diabetic retinopathy.

Statement of Benefit to California: 

Since diabetic retinopathy is a leading cause of irreversible blindness among the working age adult population in California and elsewhere, developing an effective treatment that will minimize the vision loss and blindness complications of this disorder will be a tremendous benefit to California and the world. Working age adults with diabetes mellitus may no longer become disabled due to visual impairment, allowing them to remain productive in jobs and enhance the economy of the state. In addition, since diabetes is a systemic disease involving damaged blood vessels throughout the body, the stem cell therapy developed with this proposal may be used to treat other disabling systemic complications of diabetes, such as neuropathy and kidney problems. An effective systemic therapy for diabetic complications would dramatically reduce the need for health care, and thus, reduce the cost of health care in California and the world. Furthermore, at least one member of this research team witnessed his mother blinded by retinopathy (but otherwise exceptionally healthy at 89 years old) succumb to depression caused by vision loss. The improvement in quality of life by developing effective retinopathy treatments cannot be underestimated