Treatment avenues for age-related macular degeneration: Breakthroughs and bottlenecks.

Age-related macular degeneration (AMD) is a significant factor contributing to serious vision loss in adults above 50. The presence of posterior segment barriers serves as chief roadblocks in the delivery of drugs to treat AMD. The conventional treatment strategies use is limited due to its off-targeted distribution in the eye, shorter drug residence, poor penetration and bioavailability, fatal side effects, etc. The above-mentioned downside necessitates drug delivery using some cutting-edge technology including diverse nanoparticulate systems and microneedles (MNs) which provide the best therapeutic delivery alternative to treat AMD efficiently. Furthermore, cutting-edge treatment modalities including gene therapy and stem cell therapy can control AMD effectively by reducing the boundaries of conventional therapies with a single dose. This review discusses AMD overview, conventional therapies for AMD and their restrictions, repurposed therapeutics and their anti-AMD activity through different mechanisms, and diverse barriers in drug delivery for AMD. Various nanoparticulate-based approaches including polymeric NPs, lipidic NPs, exosomes, active targeted NPs, stimuli-sensitive NPs, cell membrane-coated NPs, inorganic NPs, and MNs are explained. Gene therapy, stem cell therapy, and therapies in clinical trials to treat AMD are also discussed. Further, bottlenecks of cutting-edge (nanoparticulate) technology-based drug delivery are briefed. In a nutshell, cutting-edge technology-based therapies can be an effective way to treat AMD.

Recent Advances in Management of Neuropathic, Nociceptive, and Chronic Pain: A Narrative Review with Focus on Nanomedicine, Gene Therapy, Stem Cell Therapy, and Newer Therapeutic Options.

PURPOSE OF REVIEW: This manuscript summarizes novel clinical and interventional approaches in the management of chronic, nociceptive, and neuropathic pain. RECENT FINDINGS: Pain can be defined as a feeling of physical or emotional distress caused by an external stimulus. Pain can be grouped into distinct types according to characteristics including neuropathic pain, which is a pain caused by disease or lesion in the sensory nervous system; nociceptive pain, which is pain that can be sharp, aching, or throbbing and is caused by injury to bodily tissues; and chronic pain, which is long lasting or persisting beyond 6 months. With improved understanding of different signaling systems for pain in recent years, there has been an upscale of methods of analgesia to counteract these pathological processes. Novel treatment methods such as use of cannabinoids, stem cells, gene therapy, nanoparticles, monoclonal antibodies, and platelet-rich plasma have played a significant role in improved strategies for therapeutic interventions. Although many management options appear to be promising, extensive additional clinical research is warranted to determine best practice strategies in the future for clinicians.

Extending human healthspan and longevity: a symposium report.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.

A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

Neural Stem Cells for Early Ischemic Stroke.

Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA's thrombolytic role within the vasculature is beneficial, tPA's non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA's detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.

Free sialic acid storage disorder: Progress and promise.

Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10-100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches for FSASD.

iPSCs: A Preclinical Drug Research Tool for Neurological Disorders.

The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).

Mini-Review: Induced pluripotent stem cells and the search for new cell-specific ALS therapeutic targets.

Amongst the most important discoveries in ALS pathobiology are the works demonstrating that multiple cell types contribute to disease onset and progression. However, a significant limitation in ALS research is the inability to obtain tissues from ALS patient brain and spinal cord during the course of the disease. In vivo modeling has provided insights into the role of these cell subtypes in disease onset and progression. However, in vivo models also have shortcomings, including the reliance on a limited number of models based upon hereditary forms of the disease. Therefore, using human induced pluripotent stem cells (iPSC) reprogrammed from somatic cells of ALS patients, with both hereditary and sporadic forms of the disease, and differentiated into cell subtypes of both the central nervous system (CNS) and peripheral nervous system (PNS), have become powerful complementary tools for investigating basic mechanisms of disease as well as a platform for drug discovery. Motor neuron and other neuron subtypes, as well as non-neuronal cells have been differentiated from human iPSC and studied for their potential contributions to ALS pathobiology. As iPSC technologies have advanced, 3D modeling with multicellular systems organised in microfluidic chambers or organoids are the next step in validating the pathways and therapeutic targets already identified. Precision medicine approaches with iPSC using either traditional strategies of screening drugs that target a known pathogenic mechanism as well as "blind-to-target" drug screenings that allow for patient stratification based on drug response rather than clinical characteristics are now being employed.

Stem Cell-Derived Exosomes: a New Strategy of Neurodegenerative Disease Treatment.

Short-term symptomatic treatment and dose-dependent side effects of pharmacological treatment for neurodegenerative diseases have forced the medical community to seek an effective treatment for this serious global health threat. Therapeutic potential of stem cell for treatment of neurodegenerative disorders was identified in 1980 when fetal nerve tissue was used to treat Parkinson's disease (PD). Then, extensive studies have been conducted to develop this treatment strategy for neurological disease therapy. Today, stem cells and their secretion are well-known as a therapeutic environment for the treatment of neurodegenerative diseases. This new paradigm has demonstrated special characteristics related to this treatment, including neuroprotective and neurodegeneration, remyelination, reduction of neural inflammation, and recovery of function after induced injury. However, the exact mechanism of stem cells in repairing nerve damage is not yet clear; exosomes derived from them, an important part of their secretion, are introduced as responsible for an important part of such effects. Numerous studies over the past few decades have evaluated the therapeutic potential of exosomes in the treatment of various neurological diseases. In this review, after recalling the features and therapeutic history, we will discuss the latest stem cell-derived exosome-based therapies for these diseases.

The Progress of Stem Cell Technology for Skeletal Regeneration.

Skeletal disorders, such as osteoarthritis and bone fractures, are among the major conditions that can compromise the quality of daily life of elderly individuals. To treat them, regenerative therapies using skeletal cells have been an attractive choice for patients with unmet clinical needs. Currently, there are two major strategies to prepare the cell sources. The first is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which can recapitulate the skeletal developmental process and differentiate into various skeletal cells. Skeletal tissues are derived from three distinct origins: the neural crest, paraxial mesoderm, and lateral plate mesoderm. Thus, various protocols have been proposed to recapitulate the sequential process of skeletal development. The second strategy is to extract stem cells from skeletal tissues. In addition to mesenchymal stem/stromal cells (MSCs), multiple cell types have been identified as alternative cell sources. These cells have distinct multipotent properties allowing them to differentiate into skeletal cells and various potential applications for skeletal regeneration. In this review, we summarize state-of-the-art research in stem cell differentiation based on the understanding of embryogenic skeletal development and stem cells existing in skeletal tissues. We then discuss the potential applications of these cell types for regenerative medicine.

Overview of stem cells therapy in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons with high burden on society. Despite tremendous efforts over the last several decades, there is still no definite cure for ALS. Up to now, only two disease-modifying agents, riluzole and edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment, which only modestly improves survival and disease progression. Major challenging issues to find an effective therapy are heterogeneity in the pathogenesis and genetic variability of ALS. As such, stem cell therapy has been recently a focus of both preclinical and clinical investigations of ALS. This is because stem cells have multifaceted features that can potentially target multiple pathogenic mechanisms in ALS even though its underlying mechanisms are not completely elucidated. Methods & Results: Here, we will have an overview of stem cell therapy in ALS, including their therapeutic mechanisms, the results of recent clinical trials as well as ongoing clinical trials. In addition, we will further discuss complications and limitations of stem cell therapy in ALS. Conclusion: The determination of whether stem cells offer a viable treatment strategy for ALS rests on well-designed and appropriately powered future clinical trials. Randomized, double-blinded, and sham-controlled studies would be valuable.

Nanotechnology shaping stem cell therapy: Recent advances, application, challenges, and future outlook.

Currently, stem cell nanotechnology is one of the novel and exciting fields. Certain experimental studies conducted on the interaction of stem cells with nanostructures or nanomaterials have made significant progress. The significance of nanostructures, nanotechnology, and nanomaterials in the development of stem cell-based therapies for degenerative diseases and injuries has been well established. Specifically, the structure and properties of nanomaterials affecting the propagation and differentiation of stem cells have become a new interdisciplinary frontier in material science and regeneration medicines. In the current review, we highlight the recent major progress in this field, explore the application prospects, and discuss the issues, approaches, and challenges, to improve the applications of nanotechnology in the research and development of stem cells.

Stem cell therapy in patients with epilepsy: A systematic review.

PURPOSE: The existing evidence of the potential applications and benefits of stem cell transplantation (SCT) in people with epilepsy and also its adverse effects in humans were systematically reviewed. METHODS: MEDLINE (accessed from PubMed), Google Scholar, and Scopus from inception to August 17, 2020 were systematically reviewed for related published manuscripts. The following key words (in the title) were used: "stem cell" AND "epilepsy" OR "seizure". Articles written in English that were human studies on stem cell transplantation in people with epilepsy were all included. RESULTS: We could identify six related articles. Because of their different methodologies, performing a meta-analysis was not feasible; they included 38 adults and 81 pediatric patients together. Five studies were single-arm human studies; there were no serious adverse events in any of the studies. CONCLUSION: While stem cell transplantation seems like a promising therapeutic option for patients with drug-resistant epilepsy, data on its application is scarce and of low quality. For now, clinical stem cell-based interventions are not justified. Perhaps, in the future, there will be a rigorous and intensely scrutinized clinical trial protocol with informed consent that could provide enough scientific merit and could meet the required ethical standards.

Pluripotent stem cell-derived cardiomyocytes for treatment of cardiomyopathic damage: Current concepts and future directions.

Today, cell replacement therapy using pluripotent stem cell-derived cardiomyocytes (PSC-CMs) remains a research endeavor, with several hurdles that must be overcome before delivery of PSC-CMs can become a therapeutic reality. In this review, we highlight major findings to date from pre-clinical studies involving delivery of PSC-CMs and consider remaining challenges that must be addressed for successful clinical translation. Our goal is to provide an overview of the current status of cardiomyocyte replacement therapy and what challenges must be addressed before successful clinical translation of such therapies will be possible.

Neurogenesis After Stroke: A Therapeutic Perspective.

Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available to treat stroke are very limited. There is an urgent need to develop novel therapeutics that can effectively facilitate functional recovery. The injury that results from stroke is known to induce neurogenesis in penumbra of the infarct region. There is considerable interest in harnessing this response for therapeutic purposes. This review summarizes what is currently known about stroke-induced neurogenesis and the factors that have been identified to regulate it. Additionally, some key studies in this field have been highlighted and their implications on future of stroke therapy have been discussed. There is a complex interplay between neuroinflammation and neurogenesis that dictates stroke outcome and possibly recovery. This highlights the need for a better understanding of the neuroinflammatory process and how it affects neurogenesis, as well as the need to identify new mechanisms and potential modulators. Neuroinflammatory processes and their impact on post-stroke repair have therefore also been discussed.

A Review of Current Strategies Towards the Elimination of Latent HIV-1 and Subsequent HIV-1 Cure.

BACKGROUND: During the past 35 years, highly effective ART has saved the lives of millions of people worldwide by suppressing viruses to undetectable levels. However, this does not translate to the absence of viruses in the body as HIV persists in latent reservoirs. Indeed, rebounded HIV has been recently observed in the Mississippi and California infants previously thought to have been cured. Hence, much remains to be learned about HIV latency, and the search for the best strategy to eliminate the reservoir is the direction current research is taking. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and is applicable in human therapy is prudent for HIV eradication to be more feasible. OBJECTIVES: The main barriers preventing the cure of HIV with antiretroviral therapy have been identified, progress has been made in the understanding of the therapeutic targets to which potentially eradicating drugs could be directed, integrative strategies have been proposed, and clinical trials with various alternatives are underway. The aim of this review is to provide an update on the main advances in HIV eradication, with particular emphasis on the obstacles and the different strategies proposed. The core challenges of each strategy are highlighted and the most promising strategy and new research avenues in HIV eradication strategies are proposed. METHODS: A systematic literature search of all English-language articles published between 2015 and 2019, was conducted using MEDLINE (PubMed) and Google scholar. Where available, medical subject headings (MeSH) were used as search terms and included: HIV, HIV latency, HIV reservoir, latency reactivation, and HIV cure. Additional search terms consisted of suppression, persistence, establishment, generation, and formation. A total of 250 articles were found using the above search terms. Out of these, 89 relevant articles related to HIV-1 latency establishment and eradication strategies were collected and reviewed, with no limitation of study design. Additional studies (commonly referenced and/or older and more recent articles of significance) were selected from bibliographies and references listed in the primary resources. RESULTS: In general, when exploring the literature, there are four main strategies heavily researched that provide promising strategies to the elimination of latent HIV: Haematopoietic Stem-Cell Transplantation, Shock and Kill Strategy, Gene-specific transcriptional activation using RNA-guided CRISPR-Cas9 system, and Block and Lock strategy. Most of the studies of these strategies are applicable in vitro, leaving many questions about the extent to which, or if any, these strategies are applicable to complex picture In vivo. However, the success of these strategies at least shows, in part, that HIV-1 can be cured, though some strategies are too invasive and expensive to become a standard of care for all HIV-infected patients. CONCLUSION: Recent advances hold promise for the ultimate cure of HIV infection. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and applicable in human therapy is prudent for HIV eradication to be more feasible. Future studies aimed at achieving a prolonged HIV remission state are more likely to be successful if they focus on a combination strategy, including the block and kill, and stem cell approaches. These strategies propose a functional cure with minimal toxicity for patients. It is believed that the cure of HIV infection will be attained in the short term if a strategy based on purging the reservoirs is complemented with an aggressive HAART strategy.

[Dental stem cells: myth or hope in neuroregenerative medicine?] / Cellules souches dentaires : mythe ou espoir en médecine neurorégénératrice ?

The use of dental stem cells has raised many hopes in the development of new treatments for neurodegenerative diseases. According to current statistics, about 1 in 6 people in the world would be affected by a neurological disease. This number continues to increase as the world's population ages, making neurodegenerative diseases probably the one of the major challenges of public health in the 21st century. Neurodegenerative diseases are characterized mainly by a progressive loss of cognitive abilities and patient autonomy related to loss and degeneration of neurons in brain structures. Unfortunately, today, the only treatments available for this type of disease do only relieve the symptoms, they do not treat them, and few clinical trials have been truly convincing to date. Hence, hope lies for these diseases in the development of other therapeutic approaches. As such, dental stem cells could be a promising area of research because of their rapid growth, their great capacity for differentiation into different types of cells (among neuronal ones for some of them) and how easy they can be obtained, without raising ethical issues as for example for embryonic stem cells.

Current Status and Future Prospects of Perinatal Stem Cells.

The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.

Modelling multiple sclerosis using induced pluripotent stem cells.

Multiple Sclerosis (MS) is one of the leading causes of non-traumatic neurological disability among young adults. Due to its complex pathology and the lack of reliable disease models, there are no effective therapies for MS to prevent neurodegeneration or promote neuroprotection, and hence stop disease progression. The emergence of induced pluripotent stem cells (iPSC) has allowed the generation of patient-specific neural cell types for disease modelling, drug screening, and cell therapy. In this review, the challenges related with the use of iPSC-derived cells in MS are discussed, with a special focus on the functional studies performed, limitations and future perspectives.