Therapeutic landscape for inherited ocular diseases: Current and emerging therapies

Inherited ocular diseases comprise a heterogeneous group of rare and complex diseases, including inherited retinal diseases (IRDs) and inherited optic neuropathies. Recent success in adeno-associated virus-based gene therapy, voretigene neparvovec (Luxturna®) for RPE65-related IRDs, has heralded rapid evolution in gene therapy platform technologies and strategies, from gene augmentation to RNA editing, as well as gene agnostic approaches such as optogenetics. This review discusses the fundamentals underlying the mode of inheritance, natural history studies and clinical trial outcomes, as well as current and emerging therapies covering gene therapy strategies, cell-based therapies and bionic vision.

Focus on stem cell-based therapy for retinal degenerative diseases / 中华实验眼科杂志

Retinal degenerative diseases are the common cause of blindness for all ages.Cell replacement therapy is the main strategy for treating retinal degenerative diseases.Recently, several retinal pigment epithelium(RPE) transplantation clinical trials have taken place worldwide and greatly enhanced the visual function of patients.However, irreversible loss of photoreceptors has been found in the late stage of diseases.Thus, photoreceptor transplantation is essential for the treatment of late-stage retinal degenerative diseases.How to obtain the clinical-grade amount of human cone photoreceptors remains to be one of the technical obstacles.This review introduced the present clinical trials of RPE transplantation and research achievements of photoreceptor transplantation.Furthermore, we will focus on the studies of stem cell-derived human photoreceptor differentiation.Lastly, the difficulties and future directions of stem cell-based therapy for retinal degenerative diseases will be discussed.

Restorative Mechanism of Neural Progenitor Cells Overexpressing Arginine Decarboxylase Genes Following Ischemic Injury

Cell replacement therapy using neural progenitor cells (NPCs) following ischemic stroke is a promising potential therapeutic strategy, but lacks efficacy for human central nervous system (CNS) therapeutics. In a previous in vitro study, we reported that the overexpression of human arginine decarboxylase (ADC) genes by a retroviral plasmid vector promoted the neuronal differentiation of mouse NPCs. In the present study, we focused on the cellular mechanism underlying cell proliferation and differentiation following ischemic injury, and the therapeutic feasibility of NPCs overexpressing ADC genes (ADC-NPCs) following ischemic stroke. To mimic cerebral ischemia in vitro , we subjected the NPCs to oxygen-glucose deprivation (OGD). The overexpressing ADC-NPCs were differentiated by neural lineage, which was related to excessive intracellular calcium-mediated cell cycle arrest and phosphorylation in the ERK1/2, CREB, and STAT1 signaling cascade following ischemic injury. Moreover, the ADC-NPCs were able to resist mitochondrial membrane potential collapse in the increasingly excessive intracellular calcium environment. Subsequently, transplanted ADC-NPCs suppressed infarct volume, and promoted neural differentiation, synapse formation, and motor behavior performance in an in vivo tMCAO rat model. The results suggest that ADC-NPCs are potentially useful for cell replacement therapy following ischemic stroke.

Aplicaciones de terapias de reemplazo celular al tratamiento de enfermedades poliglutamínicas / Applications of cell replacement therapies to the treatment of poly-glutamine diseases

Se realizó una revisión de la literatura especializada con el objetivo de evaluar el estado del arte en cuanto a la aplicación de terapias de reemplazo celular en enfermedades poliglutamínicas. Se consultaron las bases de datos HighWire y PubMed, con el uso de descriptores y operadores booleanos. Se recuperaron 84 artículos sobre la temática, publicados en revistas con un factor de impacto promedio de 5,42. Se discuten los estudios experimentales y pre-clínicos realizados con relación a terapias de reemplazo celular en enfermedades poliglutamínicas. Se demuestra la efectividad del uso de células madre de distintas fuentes en el mejoramiento de la función motora en modelos experimentales de enfermedades poliglutamínicas. Se revela la necesidad de realizar estudios multicéntricos a mediano y largo plazos, para la evaluación de los efectos terapéuticos de las terapias de reemplazo celular en enfermedades poliglutamínicas.

A review of the specialized literature was carried out with the aim of evaluating the state of the art regarding the application of cell replacement therapies in polyglutamine diseases. The HighWire and PubMed databases were consulted, with the use of Boolean descriptors and operators. 84 articles were retrieved on the subject, published in journals with an average impact factor of 5.42. The experimental and pre-clinical studies carried out in relation to cell replacement therapies in polyglutamine diseases are discussed. The effectiveness of the use of stem cells from different sources in the improvement of motor function in experimental models of polyglutamine diseases is demonstrated. The need to perform multicenter studies in the medium and long term is revealed, for the evaluation of the therapeutic effects of cell replacement therapies in polyglutamine diseases.

Development of the endocrine pancreas and novel strategies for beta-cell mass restoration and diabetes therapy

Diabetes mellitus represents a serious public health problem owing to its global prevalence in the last decade. The causes of this metabolic disease include dysfunction and/or insufficient number of β cells. Existing diabetes mellitus treatments do not reverse or control the disease. Therefore, β-cell mass restoration might be a promising treatment. Several restoration approaches have been developed: inducing the proliferation of remaining insulin-producing cells, de novo islet formation from pancreatic progenitor cells (neogenesis), and converting non-β cells within the pancreas to β cells (transdifferentiation) are the most direct, simple, and least invasive ways to increase β-cell mass. However, their clinical significance is yet to be determined. Hypothetically, β cells or islet transplantation methods might be curative strategies for diabetes mellitus; however, the scarcity of donors limits the clinical application of these approaches. Thus, alternative cell sources for β-cell replacement could include embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. However, most differentiated cells obtained using these techniques are functionally immature and show poor glucose-stimulated insulin secretion compared with native β cells. Currently, their clinical use is still hampered by ethical issues and the risk of tumor development post transplantation. In this review, we briefly summarize the current knowledge of mouse pancreas organogenesis, morphogenesis, and maturation, including the molecular mechanisms involved. We then discuss two possible approaches of β-cell mass restoration for diabetes mellitus therapy: β-cell regeneration and β-cell replacement. We critically analyze each strategy with respect to the accessibility of the cells, potential risk to patients, and possible clinical outcomes.

Research progress of injected hydrogel in the treatment of myocardial infarction / 国际生物医学工程杂志

Due to myocardial necrosis and fibrous scar formation after acute myocardial infarction,patient's ventricular remodeling and cardiac function is reduced,which will cause serious impact on the long-term prognosis of patients with myocardial infarction.As new biological substitute materials,the hydrogels are superior in hydrophilicity and biocompatibility and have been widely used in the research of myocardial infarction's treatment.The hydrogels can be used alone or served as a promising cell/drug delivery vehicle.Many reports show that intramyocardial injection of hydrogels attached with stem cells and drugs can prevent left ventricle (LV) wall thinning,increase arteriole and capillary density,raise restoration ratio of implanted stem cells,facilitate controlled release of bioactive drugs,limit post-ischemic remodeling and preserve LV function in a certain extent.This article reviews injectable hydrogels research progress in the treatment of myocardial infarction.

Current status and concepts of stem cell therapy / 대한산부인과학회지

In this 21st century which is considered as the era of biotechnology, the regenerative medicine emerging as an important medical science has been expected to provide hope to patients of incurable diseases, such as myriad of degenerative disease or terminal organ failure which can not be solved until recently. Because It is also thought to be a epochal alternative therapy in every medical part including cardiovascular disease, neurological disorder, hereditary disease, liver disease, endocrine disorder, bone or cartilage disease, and skin disease, many stem cell researches are conducted and many results are reported. Stem cells are at the center of this regenerative medicine. Although there is public debate because it is inevitably associated with ethical problems like destruction of embryo or risk of reproductive cloning, stem cell research generated much interest because the expected therapeutic effect and the derived economic value would be enormous. This review will describe the characteristics of stem cell and summarize the published research results recently.

Recent Advances in Human Embryonic Stem Cell Research

The 21st century is considered as the era of Biotechnology (BT). Recently, the regenerative medicine using stem cells has been recognized as the future medicine, especially for the devastating diseases such as neurodegenerative diseases, heart disease, diabetes, infertility and liver diseases. Human embryonic stem cells (hESCs) are at the center of the stem cell research due to its ability to proliferate unlimitedly without differentiation (self-renewal) and to differentiate into the derivatives of all three germ layers including germ cells with appropriate treatments (pluripotency). A total of 173 hESC lines have been derived since the first derivation by Thomson et al. in 1998, and 70 hESC lines are currently available for distribution including hESC line (Miz-hES1) established at the MizMedi Hospital. The major goal of hESC research is to provide basic and clinical clues for cell replacement therapy, whose targets are aforementioned incurable diseases. One of the landmarks in hESC research is the derivation of a hESC line from a cloned human blastocyst, which has recently been done by Korean scientists. This made it possible to overcome the issue of immune-mediated rejection following cell replacement therapy using hESCs. Guided differentiation of hESCs into specific cell types by treating growth factors and drugs or by genetic manipulation by using overexpression or an RNAi knockdown system is one of the most active research areas. Combined efforts towards the guided differentiation of hESC into specific cell types and the cloning of hESC from a cloned human blastocyst will overcome a list of diseases hitherto considered to be incurable.

Gene and Cell Replacement via Neural Stem Cells

Neural stem cells (NSCs) are operationally defined by their ability to self-renew, to differentiate into cells of all glial and neuronal lineages throughout the neuraxis, and to populate developing or degenerating central nervous system (CNS) regions. Thus their use as graft material can be considered analogous to hematopoietic stem cell-mediated reconstitution and gene transfer. The recognition that NSCs propagated in culture could be reimplanted into mammalian brain, where they might integrate appropriately throughout the mammalian CNS and stably express foreign genes, has unveiled a new role for neural transplantation and gene therapy and a possible strategy for addressing the CNS manifestations of diseases that heretofore had been refractory to intervention. NSCs additionally have the appealing ability to home in on pathology, even over great distances. Such observations help to advance the idea that NSCs - as a prototype for stem cells from other solid organs - might aid in reconstructing the molecular and cellular milieu of maldeveloped or damaged CNS.