Funding opportunities

Recruiting stem cells for blood vessel regeneration

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06767
Funds requested: 
$3 992 890
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Peripheral arterial disease (PAD) affects 10 million Americans and the prevalence is rising due to continued growth of diabetes and aging of the population, which may result in disabling pain, nonhealing wounds and limb amputation in the absence of successful revascularization. Nearly 100,000 major amputations are performed annually in the US due to PAD, the majority occurring in diabetes. Thus, there is a major unmet need for a small caliber bypass vascular graft to treat PAD. The objective of this Development Candidate Award is to engineer nanofibrous vascular grafts with bioactive molecule to recruit endogenous stem cells and progenitor cells that can differentiate into endothelial cells and smooth muscle cells to regenerate blood vessel in vivo. This approach is based on our understanding on stem cell biology and vascular biology during vascular regeneration. We will optimize and scale up the vascular graft production in a GMP-compatible manner, perform mechanistic studies in a rat model, and complete preliminary preclinical assessment of the development candidate in a large animal model. If successful, the development of bioactive vascular grafts will open a new avenue for vascular therapy and PAD treatment to avoid limb amputation and disability, which will benefit patients and healthcare.
Statement of Benefit to California: 
Peripheral arterial disease (PAD) affects 10 million Americans and the prevalence is rising due to continued growth of diabetes and aging of the population, which may result in disabling pain, nonhealing wounds and limb amputation in the absence of successful revascularization. Nearly 100,000 major amputations are performed annually in the US due to PAD, the majority occurring in diabetes. Thus, there is a major unmet need for a small caliber bypass vascular graft to treat PAD. Up to date, there is no effective therapy for PAD. Autologous grafts such as saphenous vein are either not available due to prior use or unsuitable for vascular reconstruction due to pre-existing disease in as many as 40% of patients, and synthetic grafts have high failure rate. The development of bioactive vascular grafts will allow us to treat PAD effectively, and benefit the patients and healthcare.
Review Summary: 
This development candidate (DC) proposal aims to develop a small caliber, engineered vascular graft for the treatment of peripheral arterial disease (PAD). Autologous vein grafting, the current treatment option for this limb threatening condition, is not available for many patients as a result of pre-existing vascular disease, and available synthetic grafts may not remain open over long periods of time. The proposed graft will consist of a synthetic tubular structure coated with bioactive molecules. These molecules are intended to recruit endogenous stem cells and to prevent clotting, resulting in prolonged patency of the artificial vessels in the circulation. The applicant proposes to optimize and standardize the production and seeding of the graft, and to demonstrate proof of mechanism in a rodent model. Finally, the applicant plans to test safety and efficacy in a clinically relevant model. Objective and Milestones - The objective and Target Product Profile are clear and reasonable. The panel felt the proposed DC has a path forward into clinical trials and beyond. - Overall milestones were appropriate and clear with satisfactory success criteria. Rationale and Significance - If successfully developed, the proposed DC would produce only an incremental impact. This is a competitive space, the proposed technology is not particularly novel, and other similarly engineered vascular grafts have already reached clinical trials in low pressure, venous circulation. - Reviewers did not reach consensus regarding the need for a small caliber engineered vascular graft. - The panel questioned the choice of PAD as the first indication for the DC as grafts in these patients are subject to disease mediated restenosis. They suggested vascular access for dialysis would be a better initial indication for the technology. Feasibility and Design - Reviewers agreed that preliminary data suggest the applicant team can generate the proposed DC. - The panel debated the impact of one of the bioactive molecules upon the DCs ability to prevent platelet adhesion and maintain patency in vivo. - The panel suggested inclusion of existing prosthetics, venous conduits, or both as control groups for the relevant preclinical model studies. - Reviewers felt that the proposed preclinical model study is underpowered and unlikely to detect the intended improvement in patency. - The overall plan is appropriate for a development proposal. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI has assembled both an appropriate team and budget for the proposed work. - The level of involvement of the Co-I providing relevant clinical expertise was unclear from the proposal. Collaborations, Assets, Resources and Environment - No relevant concerns were highlighted by reviewers under this review criterion. Responsiveness to the RFA - The panel debated the extent of stem cells’ role in the proposed DC’s mechanism of action. For example, it was unclear that stem cell or progenitor cell recruitment was necessary to achieve the vascular graft.
Conflicts: 

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