Critical limb ischemia (CLI) represents a significant unmet medical need without any approved medical
therapies for patients who fail surgical or angioplasty procedures to restore blood flow to the lower leg. CLI affects 2 million people in the U.S. and is associated with an increased risk of leg amputation and death. Amputation rates in patients not suitable for surgery or angioplasty are reported to be up to 30-50% after 1 year. Patients who are not eligible for revascularization procedures are managed with palliative care, but would be candidates for the proposed Phase I clinical trial.
In an effort to combat CLI, prior and ongoing clinical trials that our group and others have conducted have evaluated direct injection of purified growth factors into the limb that has low blood flow. Some trials have tested plasmids that would produce the blood vessel growth factors for a short period of time. These therapies did show benefit in early stage clinical trials but were not significantly better than controls in Phase III (late stage) trials, probably due to the short duration of presence of the growth factors and their inability to spread to the areas most needed. Other clinical trials ongoing in our vascular center and others are testing the patient’s own stem cells, moved from the bone marrow to the damaged limb, and those studies are showing some benefit, although the final assessments are not yet completed. Stem cells can have benefit in limb ischemia because they can actively seek out areas of low oxygen and will produce some growth factors to try to encourage blood vessel growth. But in cases where the circulation needs very high levels of rescue, this strategy might not be enough.
We have discovered that mesenchymal stem/stromal cells (MSC), a type of adult stem cell, are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into damaged cells they contact. In animal models of CLI injections of MSC into the area of decreased blood flow have rapidly restored blood flow to the limbs of rodents who had zero circulation in one leg. As an improved strategy we are combining the stem cell and growth factor approaches to make a more potent therapy. We have engineered human MSCs from normal donor bone marrow to produce high levels of the strong angiogenic agent VEGF for this novel approach (MSC/VEGF). We and others have documented that MSC are capable of sustained expression of growth factors, migrate into the areas of lowest oxygen in the tissues after injection, and wrap around the damaged or tiny blood vessels to secrete their factors where they are needed most, to restore blood flow. We propose to use these MSCs as “nature’s own paramedic system”, arming them with VEGF to enhance collateral blood vessel growth.
During our first year of funding, we have successfully engineered human MSCs to produce VEGF . We shared with our collaborative funding partners (CFP) at Hospital Reina Sofia in Cordoba, Andalucía, Spain the Standard Operating Procedures developed and product required to enable them to replicate the process. We have also provided our pivotal GMP-grade VEGF lentiviral vector to their group. In addition, personnel from their laboratory came to learn our methods for MSC isolation, expansion, viral transduction, etc. Later that year, our team at UC Davis visited their facilities in Spain with the primary goal of comparing our clinical protocols. We plan to follow almost identical procedures, with the only difference being the route of administration of MSC/VEGF into patients: intramuscular injection in California and intra-arterial in Andalucia. The clinical trials in both, California and Spain will enable us to directly compare our results from the same cellular product, strengthening our conclusions.
We had a pre-preIND meeting with the Food and Drug Administration, and have performed preliminary safety and efficacy studies to test our development candidate product, MSC/VEGF. These pilot efficacy and safety studies include the following: measuring secreted VEGF levels, Examining genetic stability, performing rule-out tumorigenicity assays, conducting rule-out hemangioma and edema assays, pericyte study, retention and efficacy studies.