Early Translational IV
$4 001 027
Platelets are small, short-lived, non-nucleated cells present in the blood and are of paramount importance to prevent blood loss following injury. Low concentrations of platelets (thrombocytopenia) can lead to excessive blood loss and inability to heal wounds. Thrombocytopenia is a significant medical problem with high incidence in the US and can result from diseases such as blood disorders and cancers, certain infections such as AIDS and common medical treatments such as chemotherapy. The typical treatment for patients suffering from thrombocytopenia is the administration of donor platelets. However, patients who receive repeated doses of donor platelets often become refractory to treatment and therefore suffer a severe risk of bleeding. To treat these alloimmunized thrombocytopenic patients, we propose to utilize our expertise and technology developed over the last decade to expand and culture hematopoietic stem and progenitor cells (HSPCs) to produce high numbers of platelets that are more appropriately matched to the affected patients. As part of these studies specifically, we will optimize platelet production processes and demonstrate safety and efficacy for eventual human use.
Statement of Benefit to California:
Over 2 million platelet units are transfused yearly in the US to treat thrombocytopenia, which frequently occurs in patients suffering from a variety of cancers. In CA alone, 171,330 new cancer diagnoses are estimated for 2013. Platelet transfusion can lead to rejection due to alloimmunization and subsequently lengthened hospital stay. An alternative to donor platelets is needed to meet demand for matched platelets in alloimmune refactory thrombocytopenia. We propose to leverage our technology and experience to derive platelets from umbilical cord blood stem cells for patients refractory to receipt of unmatched donor platelets. We will work collaboratively with other companies, universities and clinicians within CA to optimize our platelet product. We firmly believe that our unique infrastructure and history of success with stem cell-based therapies combined with our collaborative and inventive culture will provide an incomparable environment to catalyze the development of therapeutics for thrombocytopenia.
This proposal aims to generate human platelets from cultured human hematopoietic stem progenitor cells (HSPCs) derived from HLA-matched sources. The proposed indication is for the treatment of patients with thrombocytopenia who suffer bleeding complications and are resistant to treatment with standard random donor platelets due to immune sensitization. The applicants propose to complete in vitro and in vivo characterization of the platelets derived from cultured HPSC in year 1 and establish GMP-compatible manufacturing methods for ex vivo platelet isolation by year 2. In year three, they intend to validate the manufacturing process, evaluate preclinical safety of product and develop a clinical plan for IND submission. Objective and Milestones - The objective of the proposal to use HSPC to create functional human platelets is clear, the approach to accomplish the objective is well defined and consistent with the well-considered Target Product Profile. - Milestones are well defined and focused to achieve a development candidate at the end of the grant Rationale and Significance - The target patient population is thrombocytopenic patients who have become refractory to random-donor platelets. Generation of HLA-matched donor platelets as an FDA approved product to address this medical need is seen as significant, but the applicants did not make a strong case for how such a product would be a more than “incremental” improvement to community-sourced HLA-matched single donor platelets. Feasibility and Design - Feasibility concerns were raised regarding the logistics of the production of the intended product for the treatment of thrombocytopenia. In particular, the reviewers expressed concern regarding the time frame required for production and characterization of the proposed product relative to the clinical scenario where the intended patient would require treatment often within a short time frame. This challenge was not sufficiently addressed in the application. - Reviewers were concerned about the scalability and yield of the current process to the level that will be required for the patient, especially should multiple doses be required given the various clinical scenarios and the short platelet half-life post-infusion. - There was additional concern about the comparative cost of this approach relative to community-derived donor platelets, economy of scale and commercial viability of such a product. - The research plan was considered sound but the overall plan was overshadowed by feasibility concerns as stated above. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI has product development experience but appeared to have limited leadership experience. - Though there are collaborators with hematology expertise listed, the percent effort of each was 5%, which was considered minimal. Collaborations, Assets, Resources and Environment - Collaborators on the project are well qualified and institutional support for project is strong Responsiveness to the RFA - Proposal was considered as responsive to the RFA - Proposal is novel but could become obsolete if methods are developed to efficiently develop platelets from pluripotent stem cells