Accelerated Repair of Vascular Injury in Diabetic Retinopathy by Autologous TGF-β-Modified Hematopoietic Stem Cells
Early Translational I
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
In this development candidate proposal, the applicant proposes to develop a treatment for diabetic retinopathy using human adult stem cells that have been activated to repair damaged vessels in the eye. The premise in this application is that a transient blockade of transforming growth factor beta (TGF-β) in hematopoietic stem cells (HSCs) will enhance the retinal repair abilities of these cells from diabetic patients. In order to achieve this goal, the applicant proposes four aims. In aim 1, the applicant will determine the optimal source of HSC by comparing their repair capability. In aim 2, the optimal route of administration will be determined. In aim 3, the applicant plans to test the vascular repair in a murine diabetic retinopathy model. Finally, in aim 4, the “long-term” (>6 month) safety of administering autologous diabetic HSCs pretreated with TGF-β will be assessed in murine models. The applicant believes these findings will be pivotal in preparation for developing an IND leading to a clinical trial in patients with diabetic retinopathy. Reviewers agreed that this proposal addresses an important problem. Diabetic retinopathy is the leading cause of vision loss in the working-age adult population and currently no therapy is available to treat this condition. One reviewer found the original observation intriguing, that a transient blockade of endogenous (TGF-β) in diabetic HSC will restore their ability to repair damaged retinal vessels in models of retinal vascular damage. However, reviewers found that the supporting data are still very preliminary and are based on a very limited number of samples from patients compared to healthy controls. Reviewers questioned the overall feasibility of the project because of a lack of detail and clarity in the experimental design. Specifically, in aim 1, the investigators plan to determine whether blood- versus bone marrow-derived HSCs are most effective when treated to block TGF-β in promoting vascular repair. One reviewer questioned whether sufficient HSCs can be obtained from the blood by the proposed methods (i.e. without mobilization). The applicant does not mention any plans for leukapheresis, and no indication of the blood volume needed to obtain sufficient cells for these studies is presented. Deceased donor bone marrow HSCs are planned, since many diabetic patients do not wish to voluntarily participate in bone marrow harvest. A reviewer expressed concern that cell characteristics may change by the time deceased donor HSCs are processed and used by investigators. In aim 3, one reviewer noted that there is insufficient information presented to give the reviewers confidence that the proposed studies in a diabetic model can be conducted for up to nine months. The applicant does not discuss treatment with insulin and if so, whether the treatment would affect the development of diabetic retinopathy. In addition, reviewers felt that if the applicant succeeded in repairing retinal ischemia in the murine diabetic model, the short observation period of six months may not be sufficient to predict what might happen in human patients. Finally, reviewers found insufficient detail provided to assess the feasibility of aim 2 for optimizing the route of delivery. Reviewers noted no mention of the retina in the experimental plan section of aim 2, but noted several references to injured cardiac tissue throughout this section of the application. All in all, reviewers found the feasibility of the proposed studies uncertain, and the application to be hastily assembled. Reviewers found that the principal investigator (PI) and key personnel have the appropriate training and experience to conduct the proposed work. Moreover, the PI has gathered a strong team of collaborators with relevant expertise and leadership in the fields of diabetic retinopathy and HSCs. Reviewers found the resources and environment appropriate for the proposed research. In summary, reviewers found the proposed concept intriguing and the PI and research team qualified, but the application was judged to suffer from insufficient preliminary supporting data and a poor experimental design.