Patient and public perspectives on cell and gene therapies: a systematic review.

Cell and gene therapies offer opportunities for treating disease with potential to restore function, and cure disease. However, they are not without risk and pose complex logistical, economic, ethical and social challenges for health systems. Here we report our systematic review of the current evidence on patient and public knowledge and perspectives of cell and gene therapies, to inform future research, education and awareness raising activities. We screened 10,735 titles and abstracts, and evaluated the full texts of 151 publications. The final selection was 35 publications. Four themes were generated from the narrative synthesis of the study findings namely: (1) Knowledge and understanding of cell and gene therapies, (2) Acceptance of cell and gene therapies (3) Understanding of risk and benefits of therapy, and (4) Information needs and current sources of information. As potential funders or future recipients, it is important that the public and patients are aware of these therapies, understand the issues involved, and can contribute to the debate. This review highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies. High quality studies exploring patient and public opinions and experiences of cell and gene therapy are required. Patient and public perceptions of these therapies, alongside evidence of clinical and cost-effectiveness, will be central to their uptake and use.

Stepping Into and Out of the Void: Funding Dynamics of Human Embryonic Stem Cell Research in California, Sweden, and South Korea.

Nonprofit organizations and philanthropists stepped into a funding void caused by controversies over public funding of human embryonic stem cell (hESC) research. Based on interviews of 83 representatives of 53 funders, we examine the motivations and accountability structures of public agencies, corporations, fundraising dependent nonprofit organizations and philanthropic organizations that funded hESC research in three jurisdictions: California, Sweden, and South Korea. While non-traditional forms of funding are essential in the early stages of research advancement, they are unreliable for the long timeframes necessary to advance cell therapies. Such funding sources may enter the field based on high expectations, but may exit just as rapidly based on disappointing rates of progress.

Four compartment method: a simplified and cost-effective method of noncultured epidermal cell suspension for the treatment of vitiligo.

BACKGROUND: Despite continued progress towards an elucidation of pathogenetic pathways in vitiligo, a definitive cure remains elusive. Noncultured epidermal cell suspension (NCECS) is emerging as the treatment of choice for surgical management of both stable and segmental vitiligo. NCECS is very effective in repigmenting stable vitiligo, but the technique requires an expert and the support of a laboratory facility. OBJECTIVES: To investigate a simplified and more cost-effective method for NCECS. METHODS: We simplified the conventional NCECS method and made it more cost-effective and simple enough to be performed in the clinic without laboratory equipment. We named this the four compartment (FC) method. Six patients with vitiligo were treated with this FC method. RESULTS: The FC method for NCECS is highly cost-effective and simple. Six patients with vitiligo were treated and the results showed marked to complete repigmentation in four patients and > 50% repigmentation in two patients in 3 months. CONCLUSIONS: The FC method is a cost-effective and simple procedure to prepare epidermal cell suspensions. In this modified method we showed that there is no need for pipette, tips, centrifuge tube and most importantly a centrifuge machine or any other expensive laboratory equipment.

Business oriented EU human cell and tissue product legislation will adversely impact Member States' health care systems.

The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.

Promising growth and investment in the cell therapy industry during the first quarter of 2012.

In the first quarter of 2012, publicly traded companies in the cell-based therapy industry continued to show promising overall growth. Highlights included $85 million in new capital investment and steady clinical trial progress.

The cell based therapy and the policy implications in India.

The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to conduct research and clinical applications of "Cell Based Therapy" (CBT) all over the world. Attempts have made in this review to discuss the current policies that are practiced by various countries in the areas related to CBT with special emphasis on CBT related research and development in India. The two major funding agencies of Government of India e.g. Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR), have jointly formulated the "Guidelines for Stem Cell Research and Therapy" in 2007 which requires update and revision. Based on the review of the current world scenario of CBT research and development, suggestions have been made for the development of a new CBT policy that will help in progress of research and patient treatment in India.

The Small- and Medium-sized Enterprises Office (SME Office) at the European Medicines Agency.

On 15 December 2005, the European Medicines Agency (EMEA) launched an "SME Office" to provide financial and administrative assistance to micro-, small- and medium-sized enterprises (SMEs), with the aim of promoting innovation and the development of new human and veterinary medicinal products by SMEs. According to current EU definition of an SME, companies with fewer than 250 employees, and an annual turnover of not more than 50 million euro or an annual balance sheet total of not more than 43 million euro, are eligible for assistance from the SME Office. Incentives available from the EMEA for SMEs, include: Administrative and procedural assistance from SME Office within the Agency; Fee reductions (90%) for scientific advice and inspections; Fee exemptions for certain administrative services (excluding parallel distribution); Deferral of the fee payable for an application for marketing authorisation or related inspection until after the grant of the marketing authorisation; Conditional fee exemption where scientific advice followed and marketing application is unsuccessful; Assistance with translations of the product information documents. At the end of May 2009, more than 380 companies from 21 countries across the European Economic Area (EEA) had SME status assigned by the EMEA. The large majority of companies are developing medicinal products for human use, 16 are veterinary companies, 15 companies are developing products for both human and veterinary use and 38 are regulatory consultants. Since the SME initiative started the Agency has processed more than 130 requests for scientific advice with fee reductions totalling of 6.9 million euro. Regulatory assistance has been provided to more than 170 companies and 12 companies have benefited from the SME translation service. Stakeholders have acknowledged the significant role the SME Office now plays as a service provider. In the period between January 2006 and June 2009, 34 applications for marketing authorization from SME applicants were filed for medicinal products for human use. Current analysis shows SMEs to have a lower success rate compared to non-SME companies. Major objections for SMEs are particularly high in the area of quality. Although the SME initiative is still at an early stage, it is apparent from the experience gained with applications for marketing authorisation to date that it is important for companies to open up an early dialogue with the EMEA. Scientific advice should be sought early, proactively and comprehensively on key issues in development (quality, non-clinical, clinical) and follow-up advice should be sought as development proceeds. For advanced therapy medicinal products, the assistance available to SMEs will be reinforced in 2009, with the introduction of the certification process.

Skeletal myoblasts as a therapeutic agent.

Cell transplantation is emerging as a new treatment designed to improve the poor outcome of patients with cardiac failure. Its rationale is that implantation of contractile cells into postinfarction scars could functionally rejuvenate these areas. Primarily for practical reasons, autologous skeletal myoblasts have been the first to be considered for a clinical use. A large number of experimental studies have consistently documented a robust engraftment of myoblasts, their in-scar differentiation into myotubes, and an associated improvement in left ventricular function. The early results of phase I clinical trials have then established both the feasibility and safety of this procedure with the caveat of arrhythmic events. Efficacy data are equally encouraging but definitely need to be validated by large prospective placebo-controlled, double-blind randomized trials such as the Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) study, the results of which are now pending. In addition to assessing the effect of myoblast transplantation on regional and global heart function, these results will also provide comprehensive safety data and thus allow a more objective assessment of the risk-benefit ratio. However, it is already apparent that the outcome of myoblast transfer could most likely be improved by optimizing the purity of the cell yield (by selecting muscle-derived progenitors less lineage-committed than the myoblasts), the mode of delivery (by increasing the accuracy of cell injections while decreasing their invasiveness), and the survival of the engrafted cells (by concomitant graft vascularization and incorporation of cells in three-dimensional matrices). Most, if not all, of these changes will have to be incorporated before skeletal myoblasts can acquire the status of therapeutic agents. Furthermore, there is increasing evidence that myoblasts may act by attenuating left ventricular remodeling or paracrinally affecting the surrounding myocardium but not by generating new cardiomyocytes because of their strict commitment to a myogenic lineage. Thus, improvement of function is not tantamount of myocardial regeneration, and if such a regeneration remains the primary objective, it is worth considering alternate cell types able to generate new cardiac cells that will be electromechanically coupled with the host cardiomyocytes. In the setting of this second generation of cells, human cardiac-specified embryonic stem cells may hold the greatest promise.

Successful transplantation of bovine testicular cells to heterologous recipients.

While heterologous germ cell transplantation was successful in pigs and goats, autologous transplantation alone has been reported to result in donor-derived spermatogenesis in cattle. The objective of this study was to investigate whether the transplantation of heterologous germ cells could result in colonization of recipient testes in cattle of different breeds. Testicular cells were isolated from 8 Bos taurus donor bull calves and then transferred into 15 Bos indicus-cross bull calves. All animals were prepubertal, donors were aged 5-7 months and recipients 5-11 months, and scrotal circumferences ranged from 15 to 22 cm. Single cell suspensions of donor testicular cells, prepared by enzymatic digestion, were labelled with fluorescent dyes PKH26 or CFDA-SE, before transfer into the rete testis of recipients under ultrasonographic guidance. To assess the longevity of colonization by donor cells, recipients were castrated 2-30 weeks after cell transfer. Donor cells were observed in 15/25 (60%) of the testes that received PKH26-labelled cells, whereas no CFDA-SE-positive cell was identified in any recipients. The maturity of the donors or recipients (measured by scrotal circumference) did not affect colonization potential. In freshly isolated tubules, clumps of PKH26-positive cells were observed, which indicated either cell division or extensive local colonization of specific areas of the tubules. In frozen sections, PKH26-positive cells were identified on the seminiferous tubule basement membrane, which indicated that these cells had successfully migrated from the tubule lumen and were likely to be spermatogonia. We conclude that PKH26 was more suitable for labelling donor testis cells and donor cells can be identified up to 6 months following transfer. These results indicate that allogeneic transplantation of testicular cells can occur between Bos taurus and Bos indicus cattle. Further studies will investigate functionality of transferred testicular cells.

Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI)--5-year follow-up.

Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI) is a new operation procedure using a cell seeded collagen matrix for the treatment of localized full-thickness cartilage defects. A prospective clinical investigation was carried out in order to clarify whether this proves suitable and confirms objective and subjective clinical improvement over a period of up to 5 years after operation. Thirty-eight patients with localised cartilage defects were treated with MACT. Within the context of clinical follow-up, these patients were evaluated for up to 5 years after the intervention. Four different scores (Meyers score, Tegner-Lysholm activity score, Lysholm-Gillquist score, ICRS score) as well as the results of six arthroscopies and biopsies obtained from four patients formed the basis of this study. For 15 patients, 5 or more years had elapsed since the operation at the time this study was completed. It was possible to obtain results 5 years postoperatively from 11 (73.3%) of these 15 patients. Overall, we included 25 patients into the evaluation with a 2-year or longer postoperative period. Five years after transplantation 8 out of 11 patients rated the function of their knee as much better or better than before. Three of the four scores showed significant improvement compared to the preoperative value. One score, the Tegner-Lysholm score showed improvement, which, however, did not prove to be significant. The significantly improved results on three scores after 5 years suggest that MACT represents a suitable but cost-intensive alternative in the treatment of local cartilage defects in the knee.

Cartilage repair with chondrocytes: clinical and cellular aspects.

Articular cartilage has a limited potential to repair. Unsatisfactory results with current treatment methods (e.g. osteochondral autografts, drilling or microfracturing) has triggered the development of new cartilage restoration techniques including autologous cell transplantation (mesenchymal stem cells or chondrocytes) with or without supporting scaffolds. Autologous chondrocyte transplantation (ACT) was first used in humans in 1987 and the first pilot was published in 1994. Two years after transplantation, 14 of the 16 patients with femoral condyle transplants had a restored joint function and 11 of 15 femoral transplants demonstrated a hyaline repair tissue. Results from patellar transplants were less encouraging. To date, we have treated over 1000 and other groups over 6000 patients. The technique gives stable long-term results with a high percentage of good to excellent results (84-90%) in patients with different types of single femoral condyle lesions, whereas in patients with other types of lesions in the knee it is less successful (average 74%). A better understanding of the repair mechanism induced by the cultured chondrocytes and the regulatory mechanisms controlling chondrogenic differentiation combined with identification and culture of stem cells with chondrogenic potential will be the key to new cartilage treatments.

The impact of regulatory policy on the development of somatic cell therapies in the United States.

Cellular therapies offer new promise for the treatment of a variety of diseases. In order to protect patients and donors, the Food and Drug Administration in the USA has been developing specific regulations. These have undergone several iterations, however, a broad-based strategy has recently emerged. These proposals are reviewed and their impact on academic institutions is assessed.

Encapsulated cell technology: from research to market.

Encapsulated cell technology has the potential to treat a wide range of diseases by the controlled and continuous delivery of biological products to the host. Many biotechnology companies have focused their interest in this technology taking into account the promising pre-clinical and clinical results and the potential clinical market. However, on the long way from clinic to market several issues will have to be addressed, including suitable scientific development, ethical obstacles, government regulations and market forces.

The growth of tissue engineering.

This report draws upon data from a variety of sources to estimate the size, scope, and growth rate of the contemporary tissue engineering enterprise. At the beginning of 2001, tissue engineering research and development was being pursued by 3,300 scientists and support staff in more than 70 startup companies or business units with a combined annual expenditure of over $600 million. Spending by tissue engineering firms has been growing at a compound annual rate of 16%, and the aggregate investment since 1990 now exceeds $3.5 billion. At the beginning of 2001, the net capital value of the 16 publicly traded tissue engineering startups had reached $2.6 billion. Firms focusing on structural applications (skin, cartilage, bone, cardiac prosthesis, and the like) comprise the fastest growing segment. In contrast, efforts in biohybrid organs and other metabolic applications have contracted over the past few years. The number of companies involved in stem cells and regenerative medicine is rapidly increasing, and this area represents the most likely nidus of future growth for tissue engineering. A notable recent trend has been the emergence of a strong commercial activity in tissue engineering outside the United States, with at least 16 European or Australian companies (22% of total) now active.