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Executive Summary The applicant proposes to establish a multi-disciplinary and multi-institutional team for allogeneic mesenchymal stem cell (MSC) therapy for the treatment of acute lung injury (ALI). Acute lung injury develops in adult and pediatric patients following trauma, shock, pneumonia, sepsis or aspiration syndrome. Currently there is no curative treatment for the disease. Proof of concept studies carried out by the Principal Investigator (PI) in ex vivo perfused human lung preparation as well as in vivo mouse model for ALI have shown benefit of MSC in reducing experimentally induced lung injury and improving survival. The applicant proposes to produce clinical grade allogeneic MSC under cGMP conditions for a regulatory filing within two years leading to a multi-center phase I and phase II clinical trial in critically ill patients with acute lung injury. There was a general agreement among the reviewers that ALI is a disease with unmet medical need. Some reviewers also agree with the scientific rationale outlined in the proposal on the use of allogeneic MSC cell therapy for the treatment of ALI, although one reviewer felt that the case for using MSC as a cellular therapy for the treatment of ALI is not compelling and pointed out that the mechanistic basis of the approach/effect is unknown. Furthermore, there is no discussion in the proposal about using other cell populations or why MSC may or may not be better than other sources of stem cells. The reviewers agreed that the PI has extensive experience in translating preclinical observations into clinical trials as evidenced by the number of Phase II and Phase III ALI clinical trials headed by the PI. He/she has nice track record of publications, including both medical and basic science journals. Consultants and contractors have been clearly defined, including members from both academia and private sector. The approach for producing human bone marrow (BM)-derived MSC under cGMP conditions for the clinical trial has been clearly defined. However, one of the reviewers wondered why the PI has not considered setting up collaboration with a company that is producing clinical grade BM-derived MSC for similar purposes. Other criticisms on the proposal included the lack of studies to optimize the dose of MSC and the delivery route. One reviewer felt that the proposed method for establishing dosing for human studies was inadequate, and suggested the use of a large animal model for that purpose instead. It was also noted that the studies proposed in the application are eligible for federal funding. Reviewer Synopsis The applicant proposes to establish a multidisciplinary network across multiple institutions focused on the utilization of allogeneic mesenchymal stem cells (MSC) as a novel cellular therapy for the treatment of acute lung in jury (ALI). The PI, who has extensive experience in clinical trials of ALI, has previously shown in studies in mice that intra-tracheal administration of MSC reduces lung injury in an E. coli endotoxin-induced model of ALI resulting in reduced pulmonary edema and increased survival. The benefits of MSC were through paracrine antiinflammatory effects and were independent of engraftment of MSC in the lung. Similar benefits of MSC were observed by the PI in a novel ex vivo perfused human lung preparation. The applicant proposes cGMP manufacture of human BM-derived MSC which is proposed as a prerequisite for their subsequent application for phase I and II clinical trials for ALI. Reviewer One Comments PI: Michael Matthay Institution: UC San Francisco Disease Target: Acute Lung Injury Concept: Allogeneic MSC for acute lung injury. 200,000 patients per year, with 75,000 deaths. Preliminary data in mouse models suggests MSC infusion can improve survival (perhaps by indirect paracrine effects). Novel “ex vivo” lung perfusate model also suggests MSC can reverse endotoxin-induced ALI. Plan is to partner with several other California institutes (Stanford, CHORI, USC). Strengths: 1. UCSF GMP facility for MSC production 2. EJ Read as consultant. 3. Rapid advancement to the clinic (predicted 2 years) 4. Good preliminary data in murine model 5. Interesting ex vivo perfusate model. 6. Impressive list of consultants/subcontractors with expertise in MSC biology, clinical production, and treatment options for ALI. A team of basic and clinical scientists, both academic and industry, is already in place. Weaknesses: 1. No discussion of why MSC may or may not be better than other sources of stem cells. 2. Further exploration of optimal delivery route needed. 3. Prior safety studies on IV infusion of MSC may not directly translate as it relates to the proposed direct lung perfusion. 4. No apparent attempt to determine optimal dose? 5. MSC research can receive federal funding. 6. Minimal details provided regarding the composition of the advisory group. Principal Investigator: PI: Dr. Matthay has been a full Professor at UCSF for over 15 years, and is PI on several grants focused on Lung injury. Included is a recently completed Phase II trial of activated protein C for treatment of ALI, since this is ending Dr. Matthay will have more free time to devote to preparation of CIRM proposal. Also of note is a current Phase III trial of aerosolized beta-2 agonists being managed through a Clinical Research Network, as well as evaluation of lung activity in brain dead organ donors. Finally, Dr. Mattthay runs a core facility to provide cells, tissues, and mouse models for ALI research. Planning Approach: Planning Approach: 1. Dr. Matthay will direct activities a. Two-day conference in August with team members b. Focus on practical details i. Harvesting, testing MSC ii. Regulatory issues iii. Plan for IND filing c. “Strong” advisory group – conference calls (video) once/month d. Second team meeting in November Reviewer Two Comments Concept: - The proposal attacks the development of a novel treatment for patients with acute lung injury effecting both adults and infants, and can be caused by trauma, shock, pneumonia, sepsis, or aspiration syndromes. Current clinical strategies for this disease include lung protective, which improves the situation but does not cure it. Promising recent studies establish in the mouse model have established that mesenchymal stem cells (MSCs) work effectively in reversing the syndrome. Preliminary data in human suggests that it might lead to the same outcome. These two facts together represent an extremely strong rationale and significance, and thus a great opportunity to translate this work in clinical trials for patients with lung injury. This is one of those projects that is scientifically ready and mature for direct human assays. - Strengths of this proposal include the importance and scientific readiness to be transferred to clinic, multidisciplinary, UCSF wonderful environment for the pursuit of this type of research. Principal Investigator: - 10% effort dedicated by PI. - Complete list of consultants and contractors has been clearly defined, including members from both academia and private sector (total of five). - The PI has an extensive curriculum. After obtaining a BA in English from Harvard, he obtained his medical degree from U Penn, did residency and research from the University of Colorado in Denver and UCSF. He has been a professor at UCSF since 1992. - Nice track record of publications, including both medical and basic science journals. Planning Approach: -The effort will include investigators from UCSF, Stanford, Childrens Hospital in Oakland, and USC – and thus is multi-institutional. - It also is multidisciplinary, in the sense that it includes researchers with expertise in immunology, cell-based therapy, and pre-clinical and clinical trials. - UCSF GMP facility will be used to culture and propagate the MSCs. - The PI estimates 6 months planning period with the milestone goal of obtaining FDA and IND within two years of the initiation of the project. - Patients in six California hospitals will be used for the clinical trials. Reviewer Three Comments Concept: • Diseases of the respiratory system collectively represent a considerable area of unmet medical need. Acute lung injury is a major cause of respiratory failure for which there has been no progress toward identifying appropriate therapies. • Although administration of MSC has been shown to alleviate symptoms in various models of lung injury, including a mouse model of ALI by the PI, the PI cites the encouraging results of clinical studies with MSC as a treatment for myocardial infarction and the alleviation of GVHD as ‘compelling evidence that human MSC have a high likely hood of being effective in the treatment of ALI”. Despite the PI’s own preclinical studies, the case for using MSC as a cellular therapy for the treatment of ALI is not compelling Principal Investigator: PI has extensive experience in translating preclinical observations into clinical studies as evidenced by: • NIH ARDS Network phase III clinical trial of beta-agonist therapy for ALI (PI Dr. Matthay is the PI) • Phase II clinical trial of Activated Protein C for ALI • Dr. Mattay is PI of an NHLBI SCCOR of ALI Collectively his role in these studies suggests he is considered an expert in the ALI field, an impression reinforced by his extensive publications in this area. The PI’s extensive experience in running clinical trials in ALI has facilitated his assembly of a multi-disciplinary team of basic and clinical scientists with an interest in developing MSC as a cellular therapy for ALI. Planning Approach: A major facet of the planning approach revolves around preparing allogeneic human bone marrow derived MSC to cGMP. While much thought has clearly gone into this it is surprising that the PI has not considered setting up a collaboration with a company that can supply clinical grade MSC (such as Osiris). A second approach is based upon preparing plans for phase I and II clinical trials across the State which will involve obtaining IRD, IRB and FDA approvals. The proposed trial will involve delivery of MSC to injured lobes of the lung of patients with ALI using a cell dose based upon the PI’s studies of MSC in the ex vivo perfused human lung model. It would seem appropriate that strong consideration should be given to developing a large animal model to establish the appropriate cell dose prior to initiating human studies.