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.
As an improved strategy we are combining the stem cell and growth factor approaches to make a more potent therapy. We have engineered human Mesenchymal Stem Cells (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 over the past 20+ years 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.
These MSC/VEGF cells are highly potent, safe and effective in our preclinical studies. The human stem cells are designed to produce VEGF as “paramedic delivery vehicles armed with growth factor" have rapidly restored blood flow to the limbs of rodents who had zero circulation in one leg. With funding that could be potentially obtained through the proposed application we will follow the detailed steps to move this candidate therapy into clinical trials, and will initiate and complete an early phase clinical trial to test safety and potential efficacy of this product that is designed to save limbs from amputation.
Critical Limb Ischemia (CLI) represents a significant unmet medical need without any curative therapies in its end stages, after even the best revascularization attempts using sophisticated catheters, stents, and bypass surgeries have failed. CLI affects over 2 million people in the US and the prevalence is increasing due to the aging of our population and the diabetes epidemic. In 2007, the treatment of diabetes and its complications in the USA generated $116 billion in direct costs; at least 33% of these costs were linked to the treatment of ischemic foot ulcers, associated with CLI. Once a patient develops CLI in a limb, the risk of needing amputation of the other limb is 50% after 6 years, with devastating consequences. Treatment costs are immense and lives are significantly shortened by this morbid disease.
The symptoms associated with this very severe form of lower extremity peripheral artery disease (PAD) are pain in the foot at rest, non- healing ulcers, limb/digital gangrene and delayed wound healing. The quality of life for those with CLI is extremely poor and reported to be similar to that of patients with end stage malignancy. Most patients with CLI will undergo repeat hospitalizations and surgical/endovascular procedures in an effort to preserve the limb, progress to immobility and need constant care. Unfortunately, the limb salvage efforts are often not effective enough, and despite multiple attempts at revascularization, the wounds still fail to heal. The final stage in 25% of cases is limb amputation, which is associated with a high mortality rate within 6 months. Amputation rates in patients not suitable for revascularization are reported to be up to 30-50% after 1 year. Fewer than half of all CLI patients achieve full mobility after an amputation and only one in four above-the-knee amputees will ever wear a prosthesis.
Between 1990–1999, over 28,000 first time lower extremity bypass procedures were performed in California for CLI, and 29% of patients were admitted to the hospital for at least one subsequent bypass operation or revision procedure. The 5-year amputation free survival rate for this group of CLI patients from California was only 51.1%. The direct costs to California for the treatment of CLI and diabetic ischemic ulcers are substantial.
The lost ability of no-option CLI patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. The goal of the proposed study is to develop and apply a safe and effective stem cell therapy to save limbs from amputation due to disorders of the vasculature that currently cannot be cured. The successful implementation of our planned therapies will significantly reduce the cost of healthcare in California and could bring people currently unable to work due to immobility back to the workforce and active lifestyles, with a significantly improved quality of life.
This goal of this proposal is to develop mesenchymal stem cells (MSCs) genetically modified to produce vascular endothelial growth factor (VEGF) for treatment of critical limb ischemia (CLI). VEGF is well known to promote the growth of new blood vessels and has been previously investigated for treatment of CLI. The investigators propose that the limited success of VEGF in previous clinical trials was due to the short duration of the presence of VEGF as a result of the method used to deliver the growth factor. To address that limitation, the investigators propose using MSCs expressing VEGF to provide a longer exposure to VEGF at the site of treatment. The project proposes to complete preclinical studies and conduct a Phase 1 clinical safety study in patients who have no other clinical treatment options.
Significance and Impact
- Reviewers agreed that CLI is a serious unmet medical need. The proposal was viewed as a high risk project but worth pursuing due to the high prevalence of this disease and the resulting increased risk of leg amputation and death.
- The Target Product Profile (TPP) was viewed as sensible and well written.
- The proposal is highly responsive to the RFA.
- Reviewers were mixed on their views of whether genetically modified MSCs would be substantially more effective than unmodified MSCs and of how significantly the modified cells would increase safety risk.
- The rationale for the project is appropriate and well presented. VEGF can cause local neovascularization and the MSCs should survive long enough to allow production of VEGF. Secretion of VEGF in a sustained manner by MSCs may improve efficacy over other delivery routes that have been explored.
-Reviewers appreciated that the genetic modification strategy for the MSCs included elements to improve safety.
- The rationale for including a cohort treated with unmodified MSCs was not clear, since MSCs have been shown to be safe in other clinical trials. It was suggested to eliminate that arm of the safety study.
- It was noted that limited duration of survival of the MSCs in vivo might require multiple administrations, rather than a single dose, to see a benefit; however starting with a single dose in the Phase 1 trial seemed sensible.
- Reviewers did not feel that the trial necessarily needed to be limited to no-option patients and suggested reconsidering the proposed patient population, possibly with input from the FDA.
Therapeutic Development Readiness
- The target has been validated, GMP material has been produced, and the team has begun the regulatory process.
-Data on safety and efficacy have been shown in preclinical studies. Given the preclinical progress, it is likely that the clinical trial indeed could be initiated in Year 3.
Feasibility of the Project Plan
- Reviewers recommended that the applicants consider whether a subset of CLI patients with a specific underlying pathology would be better responders and should be considered as an alternative to the proposed patient population.
- Concern was expressed that the preclinical GLP study was to be done using intravenous administration of cells, in contrast to the intramuscular route intended for the clinical trial. Furthermore the duration of the GLP study was viewed as likely insufficient for regulatory approval.
Principal Investigator (PI) and Development Team
- Reviewers agreed that the team is strong and has experience in CLI and successfully translating research to the clinic.
- A strength of the proposal is inclusion of consultants who are familiar with clinical gene and cell-based therapies.
Collaborations, Resources and Environment
- Excellent resources are available, including access to a GMP facility for manufacturing.
- Intellectual property resources are not well described. It was recommended that the team further explore freedom-to-operate.
Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. )
- The budget for toxicology studies does not match the work proposed.
- It was noted that some studies were to be performed using smaller GMP batches and then repeated with the clinical material. It was unclear why repeating studies were being proposed and suggested these would not be an appropriate use of CIRM funds.
- Reviewers were unclear about the activities and associated costs that would be performed in the year in between the IND filing and the beginning of patient enrollment and recommended that these activities be clarified.
- Boro Dropulic
- Darin Weber
- David Pepperl