Clinical Application and Trials with Nutraceuticals

Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair.

Perfluorocarbon liquids (PFCLs) and heavy fluorocarbon liquids (HFCLs) are being increasingly used as soft tools during vitreoretinal surgery. However, since long-term intraocular tolerance is still unsatisfactory, at present complete removal at the end of surgery is recommended. With the aim to improve long-term intraocular compatibility and to enlarge the spectrum of clinical applications, modified HFCLs have been developed. HFCL-oligomers with a higher viscosity represent the latest perspective. All three groups of fluorocarbon liquids will be compared with respect to their physical and chemical properties, experimental and clinical results, and prospects for clinical applications. Common features of PFCLs, HFCLs and HFCL-oligomers are biological inertness, specific gravity higher than water, immiscibility with water or blood, and a high gas binding capacity. In PFCLs such as decalin, octane, or phenanthrene. All carbon atoms of the carbon backbone are completely fluorinated. In experimental and clinical use, emulsification, vascular changes and structural alterations of the retina have been described. By only partial replacement of hydrogen atoms by fluorine, the specific gravity of HFCLs is reduced, whereas lipophilic properties increase. Thus HFCLs are potential solvents for intraocular silicone oil remnants. However. after long-term application, side-effects are similar to those observed with PFCLs. Substances of this group, such as F6H6, F6H8, 044, and 062 are used intraoperatively and are currently being investigated for clinical long-term application. With the aim to avoid emulsification and to improve intraocular tolerance, we have developed HFCL-oligomers consisting of 2-4 HFCL molecules with increased viscosity. The oligomers were tolerated well in rabbit eyes for up to 4 months. In contrast to PFCLs or monomers, they did not emulsify nor show vascular alterations. ERGs returned to normal after removal of the oligomer from the eye. Histology of the retina showed mild alterations. according to physical properties, experimental intraocular compatibility and stability against emulsification, HFCL-oligomers are promising candidates for improved long-term tamponade of the lower retina. At present, indications for an application in human eyes have to be determined in clinical trials.

Simple SummaryASCT2 and LAT1 are amino acid transporters whose impact in cancer has been explored throughout the years. They have been associated with most currently accepted hallmarks of cancer, thus the aim of this review is to report the impact of these transporters in this disease, as well as their clinical significance and applications. ASCT2 and LAT1 have been identified as prognostic factors and potentially as therapeutic targets. In conclusion, the study and development of new inhibitors for these amino acid transporters constitutes a promising approach towards the improvement of cancer treatment and prognosis.The role of the amino acid transporters ASCT2 and LAT1 in cancer has been explored throughout the years. In this review, we report their impact on the hallmarks of cancer, as well as their clinical significance. Overall, both proteins have been associated with cell death resistance through dysregulation of caspases and sustainment of proliferative signaling through mTOR activation. Furthermore, ASCT2 appears to play an important role in cellular energetics regulation, whereas LAT1 expression is associated with angiogenesis and invasion and metastasis activation. The molecular impact of these proteins on the hallmarks of cancer translates into various clinical applications and both transporters have been identified as prognostic factors in many types of cancer. Concerning their role as therapeutic targets, efforts have been undertaken to synthesize competitive or irreversible ASCT2 and LAT1 inhibitors. However, JHP203, a selective inhibitor of the latter, is, to the best of our knowledge, the only compound included in a Phase 1 clinical trial. In conclusion, considering the usefulness of ASCT2 and LAT1 in a variety of cancer-related pathways and cancer therapy/diagnosis, the development and testing of novel inhibitors for these transporters that could be evaluated in clinical trials represents a promising approach to cancer prognosis improvement.

Mesenchymal progenitor/stromal/stem cell (MSC) research has made substantial progress during the past decades. Investigators have published a wealth of basic science and preclinical data documenting the potential utility, efficacy, and safety of MSCs. The majority of this work has focused on the bone marrow- or adipose-derived MSCs. Since this body of evidence has set the stage for clinicians to advance from the bench to the bedside, Stem Cells International set out to publish a special issue devoted to the topic of Phases I–III Clinical Trials Using Adult Stem Cells. The result is a collection of ten outstanding articles submitted by investigators representing ten countries across Asia, Europe, and North America. In all cases, the methods section of each manuscript included a statement documenting that the clinical investigations were performed following institutional review board approval and/or that patient informed consent had been provided prior to the conduct of the study. Bieback et al. in Germany (Translating research into clinical scale manufacturing of mesenchymal stromal cells) and B. Philippe et al. in France (in “Culture and Use of Mesenchymal Stromal Cells in Phase I and II Clinical Trials”) have focused on the process of MSC isolation and expansion with respect to current Good Manufacturing Practices (cGMP). These authors highlight the state of the art as well as the challenges facing the development of clinical grade cells for therapeutic applications. From a regulatory perspective, the simplest application of MSC is to use them in the context of their tissue of origin. S. Akita et al. in Japan (in “Noncultured Autologous Adipose-Derived Stem Cell Therapy for Chronic Radiation Injury”) have exploited adipose-derived stem cells for soft tissue regeneration. They describe their clinical experience using autologous adipose-derived stem cells in combination with growth factors and scaffold to treat ten patients suffering from dermal radiation lesions. A series of three review papers from Belgium (“Phase 1–3 Clinical Trials Using Adult Stem Cells in Osteonecrosis and Nonunion Fractures” by J. –P. Hauzeur and V. Gangji), the USA and China (“Mesenchymal Progenitor Cells and Their Orthopedic Applications: Forging a Path towards Clinical Trials” by D. S. Shenaq et al.), and the Netherlands (“Clinical Applications of Human Mesenchymal Stromal Cells for Bone Tissue Engineering” by Chatterjea et al.) have examined the use of bone marrow-derived MSC for orthopedic applications. Each work provides a unique perspective on the published clinical trials using MSC to treat cartilage and tendon repair, critical sized defects, metabolic bone diseases, nonunion fractures, and/or osteonecrosis. From a public health perspective, MSC applications for common cardiac and central nervous system disorders could have substantial health and societal benefits. R. Sanz-Ruiz et al. in Spain (in “Phases I–III Clinical Trials Using Adult Stem Cells”) have emphasized the critical importance of randomized clinical trials to assess the utility of MSCs as they focus on the clinical evidence supporting MSC-based treatment of cardiac disease. Furthermore, they review the guidance documents on future clinical trials provided by a task force convened by the European Society for Cardiology. P. A. Walker et al. in the USA (in “Progenitor Cell Therapy for The Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials) provide a similar perspective relating to central nervous system disorders. They evaluate the use of bone marrow-derived MSCs for ischemic stroke, spinal cord injury, and traumatic brain injury and conclude that there remains a need for further evidence to support these clinical applications. There are potential MSC applications for metabolic disorders as well. A. C. Piscaglia et al. in Italy (in “Stem Cell Therapies for Liver Disease: State of the Art and New Perspectives) have reviewed the limited number of clinical trials using hematopoietic stem cell (HSC), MSC infusion, or cytokine (G-CSF) therapy to reverse hepatic injury due to cirrhosis, drug exposure, or other causes of end stage liver disease. Likewise, A. V. Vanikar et al. from India (in “Cotransplantation of Adipose Tissue-Derived Insulin Secreting Mesenchymal Stem Cells A Novel Therapy for Insulin-Dependent Diabetes Mellitus”) describe their experience combining adipose- and bone marrow-derived MSC to treat a cohort of 11 diabetic subjects for a period of up to 23 months. They report improved hemoglobin A1C levels as well as decreased daily requirements for exogenous insulin. Uniformly, these authors highlight both the promise and the challenges faced by this emerging field of medicine. Their manuscripts identify the critical need for additional prospective, randomized controlled clinical trials evaluating all cell-based therapies, regardless of the underlying disorder. In summary, this special issue provides a snapshot of the current status of MSC-based clinical trials across the globe. Hopefully, this publication will provide a benchmark for future meta-analyses evaluating a far greater body of clinical evidence regarding the safety and efficacy of MSC therapies. Jeffrey M. Gimble Bruce A. Bunnell Louis Casteilla Jin Sup Jung Kotaro Yoshimura

The constant outbreak of diseases caused by viral infections has caused serious harm to human health all over the world. Although many antiviral drugs have been approved for clinical use during the past decade, important issues, such as unsatisfactory efficacy, toxicity, and high cost of drugs, remain unresolved. Glycans are major components of the surfaces of both host cells and most viruses and play critical roles in the steps of viral infection. Marine glycans have more structural diversities than those found in humans. Most importantly, low toxicity and low-cost marine glycans have demonstrated potent antiviral activities through multiple molecular mechanisms. As a result, a series of marine glycan-derived agents are undergoing preclinical and clinical trials. This review discusses the recent progress in research on the marine glycan-based antiviral agents in clinical trials, relating to their structural features and clinical applications. In addition, molecular mechanisms of marine glycans involved in viral infection and novel strategies used in glycan-based drug development are critically reviewed and discussed.

Deficient adherence to trial protocols including dosing errors introduces uncertainty about the reliability of clinical trial results. Traditional ways of measuring compliance have been challenged since studies using electronic monitoring to register opening of medication containers have revealed that patient reporting and residual tablet counting tend to overestimate compliance with dosing regimens. Application to the Medical Products Agency for approval of all clinical trials performed in Sweden on medicines involving human subjects has been obligatory since 1984. The number of applications has ranged from 394 to 675 per year. Among over 1,000 clinical trial applications between May 2004 and February 2008, compliance or adherence was mentioned in the study objectives of only two applications. Clinical trial applications that combine adherence information with clinical outcome are still rare in Sweden. Phase 3 clinical trials are designed to provide sufficient evidence of efficacy to support marketing authorization. Patients are typically analyzed according to assigned group (intention to treat principle) rather than according to actual treatment received in order to ensure that an identified treatment effect is due to the treatment itself and not a result of postrandomization bias. Taking account of compliance information is therefore mainly considered as supportive evidence except for noninferiority clinical trials. However, electronic capturing of compliance information in clinical trials may have an important role in advancing our understanding of the relationship between drug dose or concentration and therapeutic efficacy or adverse reactions. Ways to optimize information from clinical trials are encouraged from a Swedish regulatory perspective and are expected to increase study efficiency.

Resolving conflicting clinical trials: Guidelines for meta-analysis

BackgroundThe set-up, activation, and delivery of clinical trials is pivotal for the advancement of medical science, serving as the primary mechanism through which new therapeutic interventions are validated for clinical use. Despite their critical role, the execution of these trials is often encumbered by a multitude of challenges. The North West London Clinical Trials Alliance (The Alliance) was established to address these complexities. It aims to bridge the gap between emerging scientific research and its clinical application through strategic collaborations among healthcare and research entities, thereby enhancing the regional ecosystem for clinical trials.Main textThis commentary aims to offer clarity on the fundamental insights that underlie The Alliance, providing a comprehensive understanding of its operational structure and the ecosystem it has fostered to optimise clinical trial delivery and revenue generation. The strategy employed by The Alliance centres on the cultivation of strategic partnerships across a broad spectrum of stakeholders. This approach addresses key operational challenges in clinical trial management, facilitating improvements in the development, setup, activation, and recruitment stages. Notably, The Alliance has reduced the average time to initiate trials to 19 days, compared to the standard 75 days typically observed for commercial setups in North West London. The effectiveness of The Alliance’s framework was notably demonstrated during the COVID-19 pandemic, particularly with the expedited recruitment performance in the Janssen COVID-19 vaccine study conducted at Charing Cross Hospital. This instance highlighted the Alliance’s capability to meet and exceed recruitment targets promptly while maintaining diversity within study cohorts. Additionally, The Alliance has effectively harnessed digital technology and infrastructure, enhancing its attractiveness to commercially funded studies and illustrating a sustainable model for clinical trial financing and execution.ConclusionThe North West London Clinical Trials Alliance represents a strategic response to the conventional challenges faced in clinical trial management, emphasising the importance of cross-sectoral collaboration and resource optimisation. Its efforts, particularly highlighted by its response to the COVID-19 pandemic, provide a case study in enhancing trial delivery and efficiency with significant implications for both regional and global clinical trials research communities.

Nanomedicines inhibiting tumor metastasis and recurrence and their clinical applications

The development of radiopharmaceuticals is essential for nuclear medicine, implementing new findings in molecular biology, drug development, and in many fields of clinical specialities, increasing its pace in particular in the field of PET and therapeutic applications. New radionuclides are emerging; an increased need of radiopharmaceuticals as companion diagnostics and new insights in targeting of in particular tumor cells open new applications in diagnosis and therapy involving radiopharmaceuticals. A major bottleneck in the process of translating new radiopharmaceuticals into clinical applications lies in the increasing regulatory burden in the pharmaceutical field in general and radioactive drugs in particular. In almost every country today, radiopharmaceuticals are considered as drugs or “medicinal products,” as the European regulations define it, whereby similar principles apply. A major principle of pharmaceutical development is the implementation of clinical trials before any new drug is considered appropriate for its intended use, aimed to ensure efficacy and safety of the product. Even though some countries allow the use of new drugs outside clinical trials, in a kind of “compassionate use” way, which has in the past been one of the major routes to bring new diagnostic and therapeutic radiopharmaceuticals into clinical application, it is not clearly regulated and has become less applicable over the last decade. Clinical trials also provide data that are recognized by authorities and also by other clinical specialities outside nuclear medicine. Such data are also an absolute requirement for commercialization of new drugs and have to be generated in a very documented way within the commercial development. Therefore, it is of ever more importance in the development of new radiopharmaceuticals to follow controlled clinical trials in the translational process from the preclinical phase to routine patient application. In this chapter the major steps required for initiating clinical trials with radiopharmaceuticals are described. As there are some formal differences between two major regulatory frameworks, Europe and the United States, recommendations are given on how to conduct clinical trials in these two regions. This chapter will cover the major regulatory background in this scenario and describe the documentation requirements and major hurdles in this process focusing on pharmaceutical issues involved.

Head and Neck Cancer Chemoprevention Gets a Shot in the Arm

Adipose-derived stem cells (ASCs) are considered a great alternative source of mesenchymal stem cells (MSCs). Unlike bone marrow stem cells (BMSCs), ASCs can be retrieved in high numbers from lipoaspirate, a by-product of liposuction procedures. Given that ASCs represent an easily accessible and abundant source of multipotent cells, ASCs have garnered attention and curiosity from both scientific and clinical communities for their potential in clinical applications. Furthermore, their unique immunobiology and secretome are attractive therapeutic properties. A decade since the discovery of a stem cell reservoir residing within adipose tissue, ASC-based clinical trials have grown over the years around the world along with assessments made on their safety and efficacy. With the progress of ASCs into clinical applications, the aim towards producing clinical-grade ASCs becomes increasingly important. Several countries have recognised the growing industry of cell therapies and have developed regulatory frameworks to assure their safety. With more research efforts made to understand their effects in both scientific and clinical settings, ASCs hold great promise as a future therapeutic strategy in treating a wide variety of diseases. Therefore, this review seeks to highlight the clinical applicability of ASCs as well as their progress in clinical trials across various medical disciplines.

Exploring biological mechanisms in orthodontic tooth movement: Bridging the gap between basic research experiments and clinical applications – A comprehensive review

Pharmaceutical regulation of genetically modified organisms (GMOs) is one of the critical issues for developing viral vector-based medicines. In this perspective, we introduce the recent improvement of regulatory operations in GMOs like viral vector-based products in Japan by comparing those in the United States and the European Union. The recent advancements in genetic modification and editing techniques have accelerated the development of advanced-therapy medicinal products using genetically modified viral vectors and cells.1 Despite the increase in use of GMOs/living modified organisms (LMOs) in medicine, the potential risk of GMOs/LMOs on the environment is a concern. To address internationally the environmental issues related to biological diversity, including the usage of GMOs/LMOs, 196 nations as of 2021 have concluded or signed the Convention on Biological Diversity (CBD), which is the first global agreement to cover all aspects of biological diversity. The Cartagena Protocol based on CBD aims to ensure the safe handling, transport, and use of GMOs/LMOs, produced by modern biotechnology, which may have an impact on biological diversity. The Cartagena Protocol was entered into force on September 11, 2003. The Cartagena Protocol requires the parties to consider the necessity of the standard of handling of GMOs/LMOs and, if necessary, to establish the standard. The EU countries had already established domestic laws based on Directive 2001/18/EC that addressed the handling of GMOs/LMOs for medical use before the establishment of the Cartagena Protocol. Therefore, the EU countries did not have to take any additional actions to regulate the handling of GMOs/LMOs for pharmaceuticals. In 2003, the Japanese government established the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms,2 known as the Cartagena Act, for the handling of the GMOs/LMOs. This Act is similar to Directive 2001/18/EC and the domestic laws established in the EU countries. In contrast to the European Union and Japan, the United States is one of the few countries that have not signed the CBD and the Cartagena Protocol. The United States enacted one specific environmental law named the National Environmental Policy Act of 1969 (NEPA) that regulates all kinds of environmental assessments. For initiating clinical trials, developers should submit appropriate clinical trial-related applications (investigational new drug (IND) application in the United States, clinical trial application (CTA) in the European Union, and clinical trial notification (CTN) in Japan) to each regulatory agency. In the European Union and Japan, approval of the usage of the GMOs/LMOs in the clinical trials is also mandatory before starting clinical trials (Figure 1). The objective of the EU domestic laws is to protect humans and the environment when carrying out deliberate release of GMOs/LMOs into the environment. Thus, developers (academia and/or industry) planning clinical trials in the EU countries should submit an environmental risk assessment (ERA) of each GMO to each country where the clinical trial will be conducted. In Japan, the Cartagena Act has two types of GMO/LMO regulations, the deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R)) and containment use for closed production sites and laboratories (Type-2 Use Regulation (T-2R)). Clinical trials are within the scope of T-1R, therefore developers planning to conduct clinical trials in Japan should submit an ERA and the T-1R application for GMOs/LMOs. In the United States, the submission of an ERA is not required for IND applications. However, when GMOs/LMOs may affect the quality of the environment, the US Food and Drug Administration (FDA) will request an ERA during the review process of the IND (the Title 21 of the Code of Federal Regulations (CFR) 25.21 and 25.31). In both the European Union and the United States, applicants should submit an ERA result of GMOs/LMOs when applying for marketing authorization, and the FDA or European Medicines Agency (EMA) reviews the appropriateness of the usage of drugs in clinical practice based on the ERA result (Figure 1). In Japan, the resubmission of an ERA is not mandatory when applying for marketing authorization. If developers obtain new data that indicates the environmental risk is lower than expected, resubmission is acceptable at any time to relax the T-1R. Some clinical researchers in Japan recently commented that the Cartagena Act delays the development of medicines containing GMOs/LMOs when compared to that of the medicines regulated by the similar laws in the European Union and the United States.3 But the regulatory framework of Japan is not significantly different from that of at least the European Union (Figure 1). The Pharmaceuticals and Medical Devices Agency (PMDA) is the Japanese regulatory agency responsible for a scientific review of new drug applications and Cartagena Act-related applications. The PMDA believed that such opinions came from the differences between the scheme of the Cartagena Act implementation and the procedure of actual development of drugs, and a lack of information on the Cartagena Act applications among academia. To solve these problems, since 2019, the Ministry of Health, Labor, and Welfare and the PMDA have started to improve the implementation of the Cartagena Act to ensure faster development of drugs (Table 1). The first improvement made in 2019 was the establishment of the PMDA official consultations to address specific measures of the Cartagena Act. The consultations for the Cartagena Act were the first established at the PMDA for the environmental law, and the developers can officially discuss the Cartagena Act-related matters with the PMDA since the establishment. It takes < 3 months to complete the official consultations and for official minutes to be published. The applicant can then submit the T-1R application as soon as the issues pointed out in the consultations are resolved. The administrative processing time after the submission is officially < 6 months, and the median actual administrative processing time and total processing time in 2021 were ~ 2.7 months and < 5 months, respectively. Section 42 of the German Drug law indicates that the evaluation period of CTA for trials dealing with GMOs/LMOs is 90 days after receiving the application conforming to the regulations. Thus, the actual administrative processing time before starting clinical trials is similar between Japan and the European Union. Since 2021, the parallel application of CTN and T-1R is acceptable. Now, developers should receive the approval of the T-1R application before at least the first patient enrollment of the clinical trial in Japan. In the European Union, several countries, such as France, accept the parallel application of CTA and ERA, but some countries, such as Poland, demand the approval of usage of the GMOs in the clinical trials before submitting a CTA.4 The PMDA has published a considerable number of instructions, such as the specific descriptions of ERA for adeno-associated virus (AAV) vectors,5 to provide information about the Cartagena Act to future applicants. The specific ERA for AAV vectors includes the general information and prior knowledge about AAVs and the general principles of risk assessment for AAV vectors. The European Commission has also published specific ERA for AAV in June 2022.6 These instructions and specific descriptions will significantly reduce the burden on applicants and regulators in Japan. Because the ERA submission is not mandatory when applying for marketing authorization, the regulation of the development of gene therapy products in Japan is not more time-consuming than that in the European Union and the United States. No funding was received for this work. The authors declared no competing interests for this work.

Replication-deficient Adenovirus Induces Host Topoisomerase I Activity: Implications for Adenovirus-mediated Gene Expression