Manufacturing with pluripotent stem cells (PSConf 2021): Key issues for future research and development

Human pluripotent stem cells (hPSC) have the capability to deliver novel cell‐based medicines that could transform medical treatments for a wide range of diseases including age‐related degenerative disorders and traumatic injury. In spite of significant investment in this area, due to the novel nature of these hPSC‐based medicines, there are challenges in almost all aspects of their manufacturing including bioprocessing, characterization and delivery. The Chinese Academy of Sciences and the Chinese Society for Stem Cell Research have collaborated to create a new discussion forum called PSConf 2021 (Pluripotent Stem Cell Conference 2021), intended to promote exchanges in communication on cutting‐edge developments and international coordination in hPSC manufacturing. The PSConf 2021 addressed crucial topics in stem cell‐based manufacturing, including stem cell differentiation, culture scale‐up, product formulation and release. This report summarizes the proceedings and conclusions from the discussion sessions, and it is accompanied by publication of individual papers from the speakers at the PSConf 2021.Significance StatementThe PSConf 2021 meeting has brought together speakers and delegates from more than 20 countries in an informal discussion forum focusing on the manufacture of cell‐based medicines using hPSCs. The conference discussion sessions enabled an open exchange of information on the latest developments, ideas on key challenges and their potential solutions. It also captured the experiences and lessons learnt by professionals who had been in the field from the earliest applications of human embryonic stem cells, and presented a diverse range of new potential pluripotent stem cell‐based medicines that are now under development, with some already in clinical trials.

Challenges in the manufacture of human plurtipotent stem cell‐based medicines.     

The new biology of ageing

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.     

Ecotoxicological assessment and dermal layer interactions of nanoparticle and its routes of penetrations

Our review focused on nanomaterials-based toxicity evaluation and its exposure to the human and aquatic animals when it was leached and contaminated in the environment. Ecotoxicological assessment and its mechanism mainly affect the skin covering layers and its preventive barriers that protect the foreign particles' skin. Nanoscale materials are essential in the medical field, especially in biomedical and commercial applications such as nanomedicine and drug delivery, mainly in therapeutic treatments. However, various commercial formulations of pharmaceutical drugs are manufactured through a series of clinical trials. The role of such drugs and their metabolites has not met the requirement of an individual's need at the early stage of the treatments except few drugs and medicines with minimal or no side effects. Therefore, biology and medicines are taken up the advantages of nano scaled drugs and formulations for the treatment of various diseases. The present study identifies and analyses the different nanoparticles and their chemical components on the skin and their effects due to penetration. There are advantageous factors available to facilitate positive and negative contact between dermal layers. It creates a new agenda for an established application that is mainly based on skin diseases.     

Drug discovery and development focusing on existing medicines: drug re-profiling strategy

As a new strategy for drug discovery and development, I focus on drug re-profiling as a way to identify new treatments for diseases. In this strategy, the actions of existing medicines, whose safety and pharmacokinetic effects in humans have already been confirmed clinically and approved for use, are examined comprehensively at the molecular level and the results used for the development of new medicines. This strategy is based on the fact that we still do not understand the underlying mechanisms of action of many existing medicines, and as such the cellular responses that give rise to their main effects and side effects are yet to be elucidated. To this extent, identification of the mechanisms underlying the side effects of medicines offers a means for us to develop safer drugs. The results can also be used for developing existing drugs for use as medicines for the treatment of other diseases. Promoting this research strategy could provide breakthroughs in drug discovery and development.     

Designed inhibitors to reduce amyloid virulence and cytotoxicity and combat neurodegenerative and infectious diseases

The review highlights the role of amyloids in various diseases and the challenges associated with targeting human amyloids in therapeutic development. However, due to the better understanding of microbial amyloids' role as virulence factors, there is a growing interest in repurposing and designing anti-amyloid compounds for antivirulence therapy. The identification of amyloid inhibitors has not only significant clinical implications but also provides valuable insights into the structure and function of amyloids. The review showcases small molecules and peptides that specifically target amyloids in both humans and microbes, reducing cytotoxicity and biofilm formation, respectively. The review emphasizes the importance of further research on amyloid structures, mechanisms, and interactions across all life forms to yield new drug targets and improve the design of selective treatments. Overall, the review highlights the potential for amyloid inhibitors in therapeutic development for both human diseases and microbial infections.     

New insights on the development of fungal vaccines: from immunity to recent challenges

Fungal infections are emerging as a major problem in part due to high mortality associated with systemic infections, especially in the case of immunocompromised patients. With the development of new treatments for diseases such as cancer and the acquired immune deficiency syndrome pandemic, the number of immunosuppressed patients has increased and, as a consequence, also the number of invasive fungal infections has increased. Several studies have proposed new strategies for the development of effective fungal vaccines. In addition, better understanding of how the immune system works against fungal pathogens has improved the further development of these new vaccination strategies. As a result, some fungal vaccines have advanced through clinical trials. However, there are still many challenges that prevent the clinical development of fungal vaccines that can efficiently immunise subjects at risk of developing invasive fungal infections. In this review, we will discuss these new vaccination strategies and the challenges that they present. In the future with proper investments, fungal vaccines may soon become a reality.     

Review: Natural Antimalarial Agents (1995-2001)

Malaria is one of the diseases for which even today not many suitable drugs are available. The rapid spread of resistance toward current drugs encourages the study for new active molecules. Ethnobotanical research can be of help to find new leads. Traditional remedies have always been a source of important antimalarial drugs and continue to provide novel and effective treatments, both where pharmaceuticals are not available and also where the disease is highly resistant to commonly prescribed drugs. This article provides a comparative compilation of various studies reported between 1995 and 2001 on natural compounds with antiplasmodial activity, with the goal of providing a basis for further in vitro and in vivo studies, as well as for clinical trials for the development of new antimalarial medicines. Referee: Dr. Robert Verpoorte, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, The Netherlands     

Compensation for cures: Why we should pay a premium for participation in ‘challenge studies’

Antibiotic resistance is one of the most pressing public health problems humanity faces. Research into new classes of antibiotics and new kinds of treatments – including risky experimental treatments such as phage therapy and vaccines – is an important part of improving our ability to treat infectious diseases. In order to aid this research, we will argue that we should permit researchers to pay people any amount of money to compensate for the risks of participating in clinical trials, including ‘challenge studies’ that involve deliberately infecting patients. We think that standard worries about paying for participation in risky research are reducible to concerns that can be addressed with the right screening mechanisms.     

Relationships between higher‐level functional capacity and dental health behaviors in community‐dwelling older adults

doi: 10.1111/j.1741‐2358.2012.00654.x Relationships between higher‐level functional capacity and dental health behaviors in community‐dwelling older adults Objective: The aim of the present study was to elucidate relationships between higher‐level functional capacity and dental health behaviours in community‐dwelling older adults. Background: In ageing society, it is necessary to promote oral health in the elderly, because good oral health is a significant contributing factor to good general health. Higher‐level functional capacity has been considered a crucial factor for successful independent living in the elderly. We hypothesised that functional capacity is a significant indicator of dental health behaviours. Methods: Three hundred and thirty‐eight adults aged 65 years or older were enrolled in this study. Higher‐level functional capacity was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG‐index). Univariate and multivariate models were constructed with dental health behaviours, such as regular visits to a dentist, brushing frequency and use of extra cleaning devices, as the dependent variable, and the total TMIG‐index score and its subcategory scores as the principal independent variable. Results: Univariate logistic regression analysis demonstrated a significant correlation between low TMIG‐index and ‘intellectual activity’ subcategory scores to lack of regular visits to a dentist and not using extra cleaning devices. Using a multivariate model, significant relationships remained after adjusting for a number of variables including demographics, medical status, lifestyle and number of remaining teeth. Conclusion: Intellectual activity of higher‐level functional capacity may be an accurate indicator of dental health behaviours in community‐dwelling older adults. Intellectual activity should be taken into consideration to effectively promote oral health behaviours and oral hygiene in elderly persons living independently.     

Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast,prostate and lung cancer

BackgroundOlder people represent increasing proportions of the population with cancer. To understand the representivity of cancer treatments in older people, we performed a systematic literature review using PRISMA guidelines of the age distribution of clinical trial participants for three leading cancer types, namely breast, prostate, and lung.MethodsWe used PubMed to identify articles detailing meta or pooled-analyses of phase III, randomised controlled trials (RCTs) of survival for breast, prostate and lung cancer, published ≤5 years from 2016. We compared the age distribution of participants to that of these cancers for “More developed regions”.Results4993 potential papers were identified, but only three papers on breast cancer, three on lung cancer, and none on prostate cancer presented the age distribution of their participants. Except for one paper of breast cancer, participants ≥70 years in all other papers were underrepresented.ConclusionsWe recommend the age distribution of patients be clearly reported in all clinical trials, as per guidelines. Clinical trials ought to be more representative of the populations most affected by the disease for which treatments are being tested. This should lead to better knowledge of effectiveness of treatments and better translation of trial results to optimal care of older cancer patients.     

Challenges in the development of glaucoma neuroprotection therapy

Glaucoma, a disease of the optic nerve and retina, causes blindness in millions of people worldwide. Currently available therapies for this disease only attempt to reduce intraocular pressure, the major risk factor, without addressing the associated optic neuropathy and retinopathy. Development of glaucoma neuroprotective treatment is therefore a pressing unmet medical need. Unfortunately, many challenges hinder this effort, including an incomplete understanding of the mechanism of pathogenesis, leading to uncertain therapeutic targets and confounded by not yet validated preclinical models. Most importantly, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy, expensive and, to many, prohibitive. No easy solution is available to overcome these challenges. Increased commitment to basic mechanistic research is an essential foundation for dealing with this problem. Innovations in clinical trials with novel surrogate endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budgetary hurdle for the development of new therapies.     

Behandeling van osteoporose bij ouderen: wat is de evidence?

Many older people, especially women, and their doctors still see osteoporosis as part of the natural course of ageing instead of as a preventable or treatable disorder. Height loss, hyperkyphosis, back pain, and fractures are accepted as consequences of ageing. The notion that it is too late to start treatment in a late stage of the disease forms another barrier to treatment. Although most studies of fracture reduction with medical treatment were not designed for the "geriatric" population, the average age of participants in most clinical trials was about 70 years. In all major studies patients also received calcium and vitamin D supplements. Nowadays, clinicians can choose from several effective treatments for the prevention of osteoporotic fractures in high-risk postmenopausal women. Data on the anti-fracture potential of calcium/vitamin D, raloxifene, bisphosphonates, strontium ralenate, and parathyroid hormone are now available. Bisphosphonates and strontium ralenate are good choices for first- or second-line treatment, while for the time being parathyroid hormone should only be used for the second-line treatment of osteoporosis in the elderly.     

呼吸道合胞病毒疫苗及其抗体制剂的研究进展

呼吸道合胞病毒(respiratory syncytial virus,RSV)感染是一个全球性的健康问题,目前临床上仍缺乏特异的治疗手段。接种疫苗主动免疫预防或使用抗体制剂被动免疫预防是避免重症感染和减少死亡的重要措施。针对不同的人群,须研制不同类型的RSV疫苗：减毒活疫苗对婴儿来说,可能是最佳选择;亚单位疫苗有引起增强型呼吸道疾病的风险,不适合RSV血清学阴性的婴幼儿接种,主要适用于老年人和孕妇。研发安全且有效的RSV疫苗难度大,虽然已有30余种RSV疫苗进入临床研究阶段,并显示出应用潜力,其中F纳米颗粒疫苗已率先进入III期临床试验,但在老年人和孕妇中未达预期效果。在RSV流行季节前,使用特异性抗体制剂也是预防高危人群严重RSV感染性疾病的有效手段。长效单克隆抗体MEDI8897比帕利珠单抗更具成本效益,已进入III期临床试验,且获得优先研发资格。多克隆免疫球蛋白RI-002已在免疫缺陷人群中显示出较好的预防效果,具有进一步研发的现实意义。本综述针对近年来RSV疫苗及其抗体的研究进展进行阐述,期望为RSV的预防提供参考。     

Finding a chink in the armor: Update,limitations, and challenges toward successful antivirals against flaviviruses

Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.     

Deciphering the enigmatic crosstalk between prostate cancer and Alzheimer's disease: A current update on molecular mechanisms and combination therapy

Alzheimer's disease (AD) and prostate cancer (PCa) are considered the leading causes of death in elderly people worldwide. Although both these diseases have striking differences in their pathologies, a few underlying mechanisms are similar when cell survival is considered. In the current study, we employed an in-silico approach to decipher the possible role of bacterial proteins in the initiation and progression of AD and PCa. We further analyzed the molecular connections between these two life-threatening diseases. The androgen deprivation therapy used against PCa has been shown to promote castrate resistant PCa as well as AD. In addition, cell signaling pathways, such as Akt, IGF, and Wnt contribute to the progression of both AD and PCa. Besides, various proteins and genes are also common in disease progression. One such similarity is mTOR signaling. mTOR is the common downstream target for many signaling pathways and plays a vital role in both PCa and AD. Targeting mTOR can be a favorable line of treatment for both AD and PCa. However, drug resistance is one of the challenges in effective drug therapy. A few drugs that target mTOR have now become ineffective due to the development of resistance. In that regard, phytochemicals can be a rich source of novel drug candidates as they can act via multiple mechanisms. This review also presents mTOR targeting phytochemicals with promising anti-PCa, anti-AD activities, and approaches to overcome the issues associated with phytochemical-based therapies in clinical trials.     

Do we protect or discriminate? Representation of senior adults in clinical trials

Aim

The analysis of barriers responsible for low recruitment of older patients in clinical trials and presentation of possible solutions are the subject of this review.

Background

Europe''s population is ageing, and the group of people who more frequently develop neoplasms increases. Oncologists are confronted with a new challenge – how to treat cancer in this group of patients, especially considering the lack of Evidence Based Medicine (EBM) guidelines for treatment of cancer in the elderly population.

Materials and methods

Medline search and analysis of studies published between 1999 and 2012, containing key words: senior adults, cancer, elderly in clinical trials.

Results

Detailed analysis of relevant studies demonstrated that senior adults are underrepresented in clinical trials. Moreover, there is a lack of trials exclusively designed for this heterogeneous group of patients. The analysis of reasons for low recruitment of older patients in clinical trials revealed barriers dependent on patient''s and physician''s attitudes as well as institutional and logistic problems.

Conclusions

It is necessary to widen the scale of trials of all phases in the group of seniors with appropriate assessment of toxicity. This will allow a proper stratification and obtaining representative groups for statistical analysis and credible trial results. Another priority is the design of trials dedicated exclusively to the elderly.     

Medical Product Development, Innovation, and Life-Cycle Regulation: The Challenges for Biostatistics

The article provides a perspective on the challenges for biostatistics as well as on contributions that biostatisticians are making and can make to medical product development and regulation and what the future might be in these areas. The current environment in the United States for pharmaceutical development and regulation is discussed along with the expectations that the public has for how medical products should contribute to public heath. The globalization of research and the use of study designs that incorporate multi-regional populations present new challenges for design and inference. The emerging interest in and development of the science of safety assessment and quantitative approaches to risk evaluation is considered. Guidance development, especially in the area of clinical trials design, continues to be one of the needs that FDA is asked to meet. Guidance development is proceeding for non-inferiority study designs, adaptive designs, multiple endpoints in clinical trials, and missing outcome data in clinical trials. Biostatisticians will be asked and challenged to take on leadership roles in new areas such as personalized medicine, biomarker and genomics, development of new tools for visual display of clinical data, quality assurance and monitoring in clinical trials.     

Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly

The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of “rare” disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed.     

Pregnancy outcomes,embryonic and fetal development in maternal exposure to chinese medicines

Chinese medicine is a common name for a collection of Chinese Materia Medica with therapeutic properties for medical treatment and healing. Similar to Western pharmaceuticals, Chinese medicines are not free of risk, and have the potential to cause adverse pregnancy outcomes and affect embryonic and fetal development. However, most clinical data concerning safety of maternal exposure to Chinese medicines during pregnancy are not available and the conclusion remains elusive. Some individual clinical trials of Chinese medicines reported some minor adverse effects during pregnancy, whereas few animal studies identified some adverse maternal and perinatal effects, as well as embryotoxic potentials. Basic research and mechanistic studies of the teratogenicity of Chinese medicines are still lacking. There is an urgent need for testing the safety of Chinese medicines before recommendation and commercialization. Until more reliable and scientific research data become available, clinicians should consider both the risks and benefits before recommending Chinese medicines to pregnant women. More systematic investigations of the safety implications of the use of Chinese medicines are highly recommended, in addition to more clinical trials with a larger sample size to confirm its safety during pregnancy. This review includes a critical overview of available clinical and experimental data and provides directions to study the safety issue of Chinese medicines for pregnancy. Birth Defects Research (Part C) 99:275–291, 2013. © 2013 Wiley Periodicals, Inc.