The Experts below are selected from a list of 71958 Experts worldwide ranked by ideXlab platform
David J. Williams - One of the best experts on this subject based on the ideXlab platform.
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Manufacturing models permitting roll out/scale out of clinically led Autologous Cell therapies: regulatory and scientific challenges for comparability
Cytotherapy, 2014Co-Authors: Paul C. Hourd, Patrick J. Ginty, Amit Chandra, David J. WilliamsAbstract:Manufacturing of more-than-minimally manipulated Autologous Cell therapies presents a number of unique challenges driven by complex supply logistics and the need to scale out production to multiple manufacturing sites or near the patient within hospital settings. The existing regulatory structure in Europe and the United States imposes a requirement to establish and maintain comparability between sites. Under a single market authorization, this is likely to become an unsurmountable burden beyond two or three sites. Unless alternative manufacturing approaches can be found to bridge the regulatory challenge of comparability, realizing a sustainable and investable business model for affordable Autologous Cell therapy supply is likely to be extremely demanding. Without a proactive approach by the regulators to close this “translational gap,” these products may not progress down the development pipeline, threatening patient accessibility to an increasing number of clinician-led Autologous Cellular therapies that are already demonstrating patient benefits. We propose three prospective manufacturing models for the scale out/roll out of more-than-minimally manipulated clinically led Autologous Cell therapy products and test their prospects for addressing the challenge of product comparability with a selected expert reference panel of US and UK thought leaders. This paper presents the perspectives and insights of the panel and identifies where operational, technological and scientific improvements should be prioritized. The main purpose of this report is to solicit feedback and seek input from key stakeholders active in the field of Autologous Cell therapy in establishing a consensus-based manufacturing approach that may permit the roll out of clinically led Autologous Cell therapies.
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Qualification of academic facilities for small-scale automated manufacture of Autologous Cell-based products.
Regenerative medicine, 2014Co-Authors: Paul C. Hourd, Patrick J. Ginty, Amit Chandra, David Alvey, Mark J.s. Mccall, Elizabeth Ratcliffe, Erin A. Rayment, David J. WilliamsAbstract:Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of Autologous Cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic Cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of Autologous Cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned.
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Regulatory challenges for the manufacture and scale-out of Autologous Cell therapies
StemBook, 2014Co-Authors: Paul C. Hourd, Amit Chandra, Nick Medcalf, David J. WilliamsAbstract:While many clinician- and industry-led Autologous Cellular therapies are demonstrating benefits to patients in clinical trials, few products have been commercially approved. Progress towards production and commercialization still faces substantial translational challenges under existing regulatory frameworks. Manufacturing and supply of more-than-minimally manipulated (MTMM) Autologous Cell based therapies presents a number of unique challenges driven by complex supply logistics and the need to scale-out production to multiple manufacturing sites or potentially near to the patient within hospital settings. The existing regulatory structure in Europe and the U.S imposes a requirement to establish and maintain comparability. Under a single market authorisation this is likely to become an insurmountable burden for the roll-out of manufacturing processes to more than two or three sites unless new enabling manufacturing and regulatory science can be established to bridge the comparability challenge.
Roy Y. Calne - One of the best experts on this subject based on the ideXlab platform.
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characterization of insulin secreting porcine bone marrow stromal Cells ex vivo and Autologous Cell therapy in vivo
Cell Transplantation, 2015Co-Authors: Wan Ting Loke, Vivienne Liang, Sebastian J David, Wai Har Ng, Heng Nung Koong, Roy Y. CalneAbstract:: Cell therapy could potentially meet the need for pancreas and islet transplantations in diabetes mellitus that far exceeds the number of available donors. Bone marrow stromal Cells are widely used in clinical trials mainly for their immunomodulatory effects with a record of safety. However, less focus has been paid to developing these Cells for insulin secretion by transfection. Although murine models of diabetes have been extensively used in gene and Cell therapy research, few studies have shown efficacy in large preclinical animal models. Here we report optimized conditions for ex vivo expansion and characterization of porcine bone marrow stromal Cells and their permissive expression of a transfected insulin gene. Our data show that these Cells resemble human bone marrow stromal Cells in surface antigen expression, are homogeneous, and can be reproducibly isolated from outbred Yorkshire-Landrace pigs. Porcine bone marrow stromal Cells were efficiently expanded in vitro to >10(10) Cells from 20 ml of bone marrow and remained karyotypically normal during expansion. These Cells were electroporated with an insulin expression plasmid vector with high efficiency and viability, and secreted human insulin and C-peptide indicating appropriate processing of proinsulin. We showed that Autologous insulin-secreting bone marrow stromal Cells implanted and engrafted in the liver of a streptozotocin-diabetic pig that modeled type 1 diabetes resulted in partial, but significant, improvement in hyperglycemia that could not be ascribed to regeneration of endogenous β-Cells. Glucose-stimulated insulin secretion in vivo from implanted Cells in the treated pig was documented by a rise in serum human C-peptide levels during intravenous glucose tolerance tests. Compared to a sham-treated control pig, this resulted in significantly reduced fasting hyperglycemia, a slower rise in serum fructosamine, and prevented weight loss. Taken together, this study suggests that bone marrow stromal Cells merit further development as Autologous Cell therapy for diabetes.
Gian Paolo Fadini - One of the best experts on this subject based on the ideXlab platform.
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Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies
Circulation research, 2017Co-Authors: Mauro Rigato, Matteo Monami, Gian Paolo FadiniAbstract:Rationale: Critical limb ischemia is a life-threatening complication of peripheral arterial disease. In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death. Objective: To provide a systematic review of the literature and a meta-analysis of studies evaluating safety and efficacy of Autologous Cell therapy for intractable peripheral arterial disease/critical limb ischemia. Methods and Results: We retrieved 19 randomized controlled trials (837 patients), 7 nonrandomized trials (338 patients), and 41 noncontrolled studies (1177 patients). The primary outcome was major amputation. Heterogeneity was high, and publication bias could not be excluded. Despite these limitations, the primary analysis (all randomized controlled trials) showed that Cell therapy reduced the risk of amputation by 37%, improved amputation-free survival by 18%, and improved wound healing by 59%, without affecting mortality. Cell therapy significantly increased ankle brachial index, increased transcutaneous oxygen tension, and reduced rest pain. The secondary analysis (all controlled trials; n=1175 patients) shows that there may be potential to avoid ≈1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2332 patients) precisely estimated the changes in ankle brachial index, transcutaneous oxygen tension, rest pain, and walking capacity after Cell therapy. Intramuscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear Cells may outperform bone marrow–mononuclear Cells and mesenchymal stem Cells. Amputation rate was improved more in trials wherein the prevalence of diabetes mellitus was high. Cell therapy was not associated with severe adverse events. Remarkably, efficacy of Cell therapy on all end points was no longer significant in placebo-controlled randomized controlled trials and disappeared in randomized controlled trials with a low risk of bias. Conclusions: Although this meta-analysis highlights the need for more high-quality placebo-controlled trials, equipoise may no longer be guaranteed because Autologous Cell therapy has the potential to modify the natural history of intractable critical limb ischemia.
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Autologous stem Cell therapy for peripheral arterial disease meta analysis and systematic review of the literature
Atherosclerosis, 2010Co-Authors: Gian Paolo Fadini, Carlo Agostini, Angelo AvogaroAbstract:Background: Peripheral arterial disease (PAD) is a common cause of disability and mortality. Up to one third of patients are not susceptible to traditional revascularization and may benefit from stem Cell therapies. Objective: In this meta-analysis, we sought to determine whether Autologous Cell therapy is effective in the treatment of PAD. Methods: We searched the English literature in Medline, Excerpta Medica and the Cochrane database for trials of Autologous Cell therapy in patients with PAD published before 31 January 2009. We included controlled and non-controlled, randomized and non-randomized trials using Autologous bone marrow or granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood Cells to treat PAD. We also collected data from trials of G-CSF monotherapy, as a control treatment. Results: In a meta-analysis of 37 trials, Autologous Cell therapy was effective in improving surrogate indexes of ischemia, subjective symptoms and hard endpoints (ulcer healing and amputation). On the contrary, G-CSF monotherapy was not associated with significant improvement in the same endpoints. Patients with thromboangiitis obliterans showed some larger benefits than patients with atherosclerotic PAD. The intramuscular route of administration and the use of bone marrow Cells seemed somehow more effective than intrarterial administration and the use of mobilized peripheral blood Cells. The procedures were well tolerated and generally safe. Conclusion: This meta-analysis indicates that intramuscular Autologous bone marrow Cell therapy is a feasible, relatively safe and potentially effective therapeutic strategy for PAD patients, who are not candidate for traditional revascularization. Larger, placebo-controlled, randomized multicenter trials need to be planned and conducted to confirm these findings.
Marco Stampanoni - One of the best experts on this subject based on the ideXlab platform.
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prenatally engineered Autologous amniotic fluid stem Cell based heart valves in the fetal circulation
Biomaterials, 2012Co-Authors: Benedikt Weber, Maximilian Y Emmert, Luc Behr, Roman Schoenauer, Chad Brokopp, Cord Drogemuller, Peter Modregger, Marco StampanoniAbstract:Prenatal heart valve interventions aiming at the early and systematic correction of congenital cardiac malformations represent a promising treatment option in maternal-fetal care. However, definite fetal valve replacements require growing implants adaptive to fetal and postnatal development. The presented study investigates the fetal implantation of prenatally engineered living Autologous Cell-based heart valves. Autologous amniotic fluid Cells (AFCs) were isolated from pregnant sheep between 122 and 128 days of gestation via transuterine sonographic sampling. Stented trileaflet heart valves were fabricated from biodegradable PGA-P4HB composite matrices (n = 9) and seeded with AFCs in vitro. Within the same intervention, tissue engineered heart valves (TEHVs) and unseeded controls were implanted orthotopically into the pulmonary position using an in-utero closed-heart hybrid approach. The transapical valve deployments were successful in all animals with acute survival of 77.8% of fetuses. TEHV in-vivo functionality was assessed using echocardiography as well as angiography. Fetuses were harvested up to 1 week after implantation representing a birth-relevant gestational age. TEHVs showed in vivo functionality with intact valvular integrity and absence of thrombus formation. The presented approach may serve as an experimental basis for future human prenatal cardiac interventions using fully biodegradable Autologous Cell-based living materials.
Paul C. Hourd - One of the best experts on this subject based on the ideXlab platform.
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Manufacturing models permitting roll out/scale out of clinically led Autologous Cell therapies: regulatory and scientific challenges for comparability
Cytotherapy, 2014Co-Authors: Paul C. Hourd, Patrick J. Ginty, Amit Chandra, David J. WilliamsAbstract:Manufacturing of more-than-minimally manipulated Autologous Cell therapies presents a number of unique challenges driven by complex supply logistics and the need to scale out production to multiple manufacturing sites or near the patient within hospital settings. The existing regulatory structure in Europe and the United States imposes a requirement to establish and maintain comparability between sites. Under a single market authorization, this is likely to become an unsurmountable burden beyond two or three sites. Unless alternative manufacturing approaches can be found to bridge the regulatory challenge of comparability, realizing a sustainable and investable business model for affordable Autologous Cell therapy supply is likely to be extremely demanding. Without a proactive approach by the regulators to close this “translational gap,” these products may not progress down the development pipeline, threatening patient accessibility to an increasing number of clinician-led Autologous Cellular therapies that are already demonstrating patient benefits. We propose three prospective manufacturing models for the scale out/roll out of more-than-minimally manipulated clinically led Autologous Cell therapy products and test their prospects for addressing the challenge of product comparability with a selected expert reference panel of US and UK thought leaders. This paper presents the perspectives and insights of the panel and identifies where operational, technological and scientific improvements should be prioritized. The main purpose of this report is to solicit feedback and seek input from key stakeholders active in the field of Autologous Cell therapy in establishing a consensus-based manufacturing approach that may permit the roll out of clinically led Autologous Cell therapies.
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Qualification of academic facilities for small-scale automated manufacture of Autologous Cell-based products.
Regenerative medicine, 2014Co-Authors: Paul C. Hourd, Patrick J. Ginty, Amit Chandra, David Alvey, Mark J.s. Mccall, Elizabeth Ratcliffe, Erin A. Rayment, David J. WilliamsAbstract:Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of Autologous Cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic Cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of Autologous Cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned.
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Regulatory challenges for the manufacture and scale-out of Autologous Cell therapies
StemBook, 2014Co-Authors: Paul C. Hourd, Amit Chandra, Nick Medcalf, David J. WilliamsAbstract:While many clinician- and industry-led Autologous Cellular therapies are demonstrating benefits to patients in clinical trials, few products have been commercially approved. Progress towards production and commercialization still faces substantial translational challenges under existing regulatory frameworks. Manufacturing and supply of more-than-minimally manipulated (MTMM) Autologous Cell based therapies presents a number of unique challenges driven by complex supply logistics and the need to scale-out production to multiple manufacturing sites or potentially near to the patient within hospital settings. The existing regulatory structure in Europe and the U.S imposes a requirement to establish and maintain comparability. Under a single market authorisation this is likely to become an insurmountable burden for the roll-out of manufacturing processes to more than two or three sites unless new enabling manufacturing and regulatory science can be established to bridge the comparability challenge.
