Translating stem cell research into development of cellular drugs-a perspective from manufacture of stem cell products and CMC considerations.

The development of human pluripotent stem cell (PSC)-derived medicinal products has been gathering steam in recent years, but the translation of research protocols into GMP production remains a daunting task. The challenges not only reside with the nature of cellular therapeutics but are also rooted in the general inexperience in industry-scale production of stem cell products. Manufacturers of PSC-derived products should be aware of the technical nuances and take a holistic approach toward early planning and engagement with their academic partners. While not all issues will be readily resolved soon, the collective knowledge and consensus by the manufacturers and key stakeholders will help to guide rapid progression of the field.

Novel insights and innovations in biotechnology towards improved quality of life.

Resolution of old problems with new tools seems to be a new way of challenging and finding the keys to innovation. A holistic view of different branches of science and industry, including services for society, is critically important for the development of modern science. The International Congress Eurobiotech 2017 was a special opportunity for such a universal view. In this paper, we discuss the application of different small RNAs, stem cells, epigenetics and sequencing, as well as art and bioeconomy. Our most significant message is not a new one but is very universal: biotechnology is vital for society.

Stem Cell Technology for (Epi)genetic Brain Disorders.

Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research.

Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age- and immune-system-related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high-quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off-site effects of the intervention. Stem Cells 2017;35:1141-1153.

Stem cells and interspecies chimaeras.

Chimaeras are both monsters of the ancient imagination and a long-established research tool. Recent advances, particularly those dealing with the identification and generation of various kinds of stem cells, have broadened the repertoire and utility of mammalian interspecies chimaeras and carved out new paths towards understanding fundamental biology as well as potential clinical applications.

Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders.

Monogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases, transcriptional activator-like effector nucleases, and the clustered regulatory interspaced short palindromic repeat/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations.

Neurodegenerative diseases in a dish: the promise of iPSC technology in disease modeling and therapeutic discovery.

The study of stem-cell biology has been a flourishing research area because of its multi-differentiation potential. The emergence of induced pluripotent stem cells (iPSCs) open up the possibility of addressing obstructs, such as the limited cell source, inherent complexity of the human brain, and ethical constrains. Though still at its infancy phase, reprogramming of somatic cells has been demonstrating the ability to enhance in vitro study of neurodegenerative diseases and potential treatment. However, iPSCs would not thoroughly translate to the clinic before limitations are addressed. In this review, by summarizing the recent development of iPSC-based models, we will discuss the feasibility of iPSC technology on relevant diseases depth and illustrate how this new tool applies to drug screening and celluar therapy.

Regenerative medicine: transforming the drug discovery and development paradigm.

Despite the explosion of knowledge in basic biological processes controlling tissue regeneration and the growing interest in repairing/replacing diseased tissues and organs through various approaches (e.g., small and large molecule therapeutics, stem cell injection, tissue engineering), the pharmaceutical industry (pharma) has been reluctant to fully adopt these technologies into the traditional drug discovery and research and development (R&D) process. In this article, I discuss knowledge-base gaps and other possible factors that may delay full incorporation of these innovations in pharma R&D. I hope that this discussion will illuminate key issues that currently limit synergistic relationships between pharma and academic institutions and may even stimulate initiation of such collaborative research.

Cuestiones éticas y normativas de las investigaciones y terapias con células madre / Ethical and legal issues of stem cell research and therapy

Las investigaciones con células madre representan un desarrollo de vanguardia en la investigación biomédica que puede ofrecer un medio eficaz para tratar enfermedades que actualmente tienen pocas o ninguna opción de tratamiento. Estos avances han generado nuevas áreas para la investigación tanto a nivel académico como industrial y han planteado nuevos desafíos para la actual regulación de productuos terapéuticos. En el ámbio ético-jurídico, la investigación con células madre plantea dos grandes campos de problemas: los derivados de su obtención y los inherentes a su utilización. El marco normativo creado para regular una y otra problemática se ha efectuado por separado en la mayoría de las legislaciones nacionales, dado que comprometen decisiones normativas de diferente jerarquía. Identificaremos las principales cuestiones, tendencias y soluciones normativas que se plan teas a partir de estas nuevas tecnologías...

Bringing prosocial values to translational, disease-specific stem cell research.

BACKGROUND: Disease-specific stem cell therapies, created from induced pluripotent stem cell lines containing the genetic defects responsible for a particular disease, have the potential to revolutionize the treatment of refractory chronic diseases. Given their capacity to differentiate into any human cell type, these cell lines might be reprogrammed to correct a disease-causing genetic defect in any tissue or organ, in addition to offering a more clinically realistic model for testing new drugs and studying disease mechanisms. Clinical translation of these therapies provides an opportunity to design a more systematic, accessible and patient-influenced model for the delivery of medically innovative treatments to chronically ill patients. DISCUSSION: I focus on disease-specific cell therapies because the types of patients who would benefit from them have congenital, severe, high-maintenance chronic conditions. They accordingly have a very strong claim for medical need and therapeutic intervention, must interact regularly with health providers, and so have the greatest stake in influencing, at a systemic level, the way their care is delivered. Given such patients' shared, aggregate needs for societal support and access to medical innovation, they constitute "patient communities". To reify the relevance of patient communities within a clinical context, I propose competitive grants or "prizes" to spur innovation in delivery of care, promoting "prosocial" values of transparency, equity, patient empowerment, and patient-provider and inter-institutional collaboration. As facilitators of participant-driven advocacy for health and quality of life-improving measures, patient communities may be synergistic with the broad-based, geo-culturally embedded public health networks typically referred to as "communities" in the public health literature. SUMMARY: Prosocial values acquire a strong ethical justification based on shared need, and can be clearly defined as grant criteria, when applied to patients such as those who will benefit from disease-specific stem cell treatments. Within this context, prosociality aims not just to expand patients' treatment choices, but also their opportunities to take a more active role in the management of their own care and contribute towards shared goals through better-informed advocacy. Accordingly, prosociality promotes relational autonomy as well as other basic bioethical principles, including beneficence and a holistic, relational conception of human dignity.

Great expectations: autism spectrum disorder and induced pluripotent stem cell technologies.

New applications of iPSC technology to research on complex idiopathic conditions raise several important ethical and social considerations for potential research participants and their families. In this short review, we examine these issues through the lens of emerging research on autism spectrum disorder (ASD). We begin by describing the current state of iPSC technology in research on ASD. Then we discuss how the social history of and current controversies in autism research combined with the emergence of autism-specific iPSC biobanks indicate an urgent need for researchers to clearly communicate the limitations and possibilities of iPSC research to ensure research participants have the ability to provide fully informed, voluntary consent. We conclude by offering recommendations to bolster informed consent for research involving iPSC biobanks, both in the specific context of ASD and more broadly.

ICT and mobile health to improve clinical process delivery. a research project for therapy management process innovation.

The volume and the complexity of clinical and administrative information make Information and Communication Technologies (ICTs) essential for running and innovating healthcare. This paper tells about a project aimed to design, develop and implement a set of organizational models, acknowledged procedures and ICT tools (Mobile & Wireless solutions and Automatic Identification and Data Capture technologies) to improve actual support, safety, reliability and traceability of a specific therapy management (stem cells). The value of the project is to design a solution based on mobile and identification technology in tight collaboration with physicians and actors involved in the process to ensure usability and effectivenes in process management.

Communicating risks and benefits about ethically controversial topics: the case of induced pluripotent stem (iPS) cells.

Many are supportive of approaches that incorporate lay citizens into policy making and risk management decisions. However, a great deal of learning must first take place about how citizen engagement for controversial topics is best accomplished. Online risk communication efforts are increasing in popularity but there is little empirical evidence accrued to demonstrate the effectiveness of such methods. The intention of our overall study is to create a powerful method for in-depth two-way communication with the public and expert communities about complex and sensitive issues at the heart of stem cell (SC) research. The fundamental objective is to raise awareness of SC science with lay citizens by fostering more holistic or "all things considered" ethical judgments. Our risk communication study demonstrates that lay citizens are both interested in, and capable of learning about, complex scientific issues provided the right tools are used to convey information and assess understanding. Our results show that it is worth the time and effort for SC researchers to continue posting podcasts and FAQ's about their work for non-expert communities to view. In addition, despite having increased our participants' risk perceptions about induced pluripotent stem (iPS) cell research, almost all were very supportive of this type of research in Canada by the end of the survey. In other words, participants understood that this research did in fact pose some risks and learned a great deal about both the risks and benefits of iPS cell research, and still thought this research was worthwhile to pursue.

Translation of stem cell research: points to consider in designing preclinical animal studies.

Stem cell-based therapies hold tremendous promise for the treatment of serious diseases and injuries. Although hematopoietic stem cell transplantation is routinely used as part of the treatment regime for some malignancies and genetic diseases, most stem cell-based therapeutic products are investigational and still require preclinical and clinical studies to support their many novel therapeutic uses. Because of the multiple sources of stem cells, the plethora of potential applications, and the novel mechanism of action of stem cell-based therapies, there is no single set of universal guidance documents that can be used to inform the preclinical development path for these therapeutics. Specific technical issues relating to the transplantation of human cells in animals, new delivery procedures, and laborious methods to characterize transplanted cells can present further challenges in the design and execution of preclinical animal studies for stem cell-based therapeutic products. In this article, we outline important parameters to guide the design of preclinical studies for stem cell-based therapeutics. In addition, we review the types of preclinical studies that should be considered depending on the nature and specific use of the intended stem cell therapeutic product. Finally, we describe important considerations in the design and execution of specific studies to monitor the efficacy, toxicity, biodistribution, and tumorigenicity of stem cell-based therapeutics.

The international translational regenerative medicine center.

The International Translational Regenerative Medicine Center, an organizing sponsor of the World Stem Cell Summit 2012, is a global initiative established in 2011 by founding partners Karolinska Institutet (Stockholm, Sweden) and Beckman Research Institute at City of Hope (CA, USA) with a mission to facilitate the acceleration of translational research and medicine on a global scale. Karolinska Institutet, home of the Nobel Prize in Medicine or Physiology, is one of the most prestigious medical research institutions in the world. The Beckman Research Institute/City of Hope is ranked among the leading NIH-designated comprehensive cancer research and treatment institutions in the USA, has the largest academic GMP facility and advanced drug discovery capability, and is a pioneer in diabetes research and treatment.

Stem cell-based therapies: promises, obstacles, discordance, and the agora.

Stem cell research has entered the public consciousness through the media. Proponents and opponents of all such research, or of human embryonic stem cell research specifically, engage in heated exchanges in the modern public forum where stakeholders negotiate, the agora. One common claim that emerges from the fray is that a particular type of stem cell research should be pursued as the most promising path toward the reduction of suffering and untimely death for all of humanity. Upon evaluation, experimental data regarding the potential role of stem cells in regenerative therapies for three conditions-spinal cord injury, type 1 diabetes, and cardiovascular disease-tell distinct, complex, and inconclusive stories. Further analyses in this article incorporate realistic considerations of a broad range of relevant factors: limited funding for biomedical research, media motives, the discordance hypothesis of evolutionary medicine, the relationship between religion and science, medical care in developing nations, and culture wars over abortion. Holistic investigation inspired by the current agora conversation supports the need to drastically change interactions regarding stem cell research so that its potential to benefit humanity may be more fully realized.

Stem Cells in Drug Screening for Neurodegenerative Disease

Because the average human life span has recently increased, the number of patients who are diagnosed with neurodegenerative diseases has escalated. Recent advances in stem cell research have given us access to unlimited numbers of multi-potent or pluripotent cells for screening for new drugs for neurodegenerative diseases. Neural stem cells (NSCs) are a good model with which to screen effective drugs that increase neurogenesis. Recent technologies for human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) can provide human cells that harbour specific neurodegenerative disease. This article discusses the use of NSCs, ESCs and iPSCs for neurodegenerative drug screening and toxicity evaluation. In addition, we introduce drugs or natural products that are recently identified to affect the stem cell fate to generate neurons or glia.

The continued promise of stem cell therapy in regenerative medicine.

The use of stem cells is galvanizing regenerative medicine research. An analysis of recent trends as typified by articles published between 2009 and 2010 in the journals Cell Transplantation--The Regenerative Medicine Journal and Medical Science Monitor demonstrate the increasing importance of stem cell research as being on the cutting edge of regenerative medicine research. The analysis revealed an even split between transplantation and non-transplantation studies, showing that both the applicability and general research is being pursued. New methods and tissue engineering are also highly important components of regenerative medicine as demonstrated by a number of the stem cell studies being involved with either ex vivo manipulation, or cotransplantation with other cells or biomaterials. This suggests that the best results may be achieved with adjuvant therapies. The non-transplantation studies were more focused on manipulation of transplantable agents including cells and scaffold systems, as well as the use of medicines and dietary supplements. The further elucidation of disease mechanisms was a major contribution. This analysis suggests that regenerative medicine is proceeding at a rapid pace and the next few years should be of considerable interest with the initial results of pioneering stem cell therapies being announced.

Stem cell therapy for cardiac disease: what can be learned from oncology.

Hematopoietic stem cells (HSCs) are the most well-characterized and studied stem cells. They have been used to treat various benign and malignant hematologic disorders. Most stem cell transplant recipients survive more than 5 years without any evidence of their original clinical disease. Early animal trials have demonstrated the ability to improve cardiac function by transfer of HSCs into the myocardium, and early human studies have demonstrated the feasibility and safety of this approach. Trials in patients after myocardial infarction and with chronic heart failure have seen limited and mixed success, probably because of the various cell types and methods used.