Prenatal stem cell therapy for inherited diseases: Past, present, and future treatment strategies.
Ontology highlight
ABSTRACT:
SUBMITTER: Ekblad-Nordberg A
PROVIDER: S-EPMC6988764 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Prenatal stem cell therapy for inherited diseases: Past, present, and future treatment strategies.
Ekblad-Nordberg Åsa Å Walther-Jallow Lilian L Westgren Magnus M Götherström Cecilia C
Stem cells translational medicine 20191024 2
Imagine the profits in quality of life that can be made by treating inherited diseases early in life, maybe even before birth! Immense cost savings can also be made by treating diseases promptly. Hence, prenatal stem cell therapy holds great promise for developing new and early-stage treatment strategies for several diseases. Successful prenatal stem cell therapy would represent a major step forward in the management of patients with hematological, metabolic, or immunological disorders. However, ...[more]
Similar Datasets
Project description:Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.
| S-EPMC4017118 | biostudies-literature
Project description:Research on mechanisms underlying monogenic cardiac diseases such as primary arrhythmias and cardiomyopathies has until recently been hampered by inherent limitations of heterologous cell systems, where mutant genes are expressed in noncardiac cells, and physiological differences between humans and experimental animals. Human-induced pluripotent stem cells (hiPSCs) have proven to be a game changer by providing new opportunities for studying the disease in the specific cell type affected, namely the cardiomyocyte. hiPSCs are particularly valuable because not only can they be differentiated into unlimited numbers of these cells, but they also genetically match the individual from whom they were derived. The decade following their discovery showed the potential of hiPSCs for advancing our understanding of cardiovascular diseases, with key pathophysiological features of the patient being reflected in their corresponding hiPSC-derived cardiomyocytes (the past). Now, recent advances in genome editing for repairing or introducing genetic mutations efficiently have enabled the disease etiology and pathogenesis of a particular genotype to be investigated (the present). Finally, we are beginning to witness the promise of hiPSC in personalized therapies for individual patients, as well as their application in identifying genetic variants responsible for or modifying the disease phenotype (the future). In this review, we discuss how hiPSCs could contribute to improving the diagnosis, prognosis, and treatment of an individual with a suspected genetic cardiac disease, thereby developing better risk stratification and clinical management strategies for these potentially lethal but treatable disorders.
| S-EPMC7027796 | biostudies-literature
Project description:The broad field of gene therapy promises a number of innovative treatments that are likely to become important in preventing deaths from cancer. In this review, we discuss the history, highlights and future of three different gene therapy treatment approaches: immunotherapy, oncolytic virotherapy and gene transfer. Immunotherapy uses genetically modified cells and viral particles to stimulate the immune system to destroy cancer cells. Recent clinical trials of second and third generation vaccines have shown encouraging results with a wide range of cancers, including lung cancer, pancreatic cancer, prostate cancer and malignant melanoma. Oncolytic virotherapy, which uses viral particles that replicate within the cancer cell to cause cell death, is an emerging treatment modality that shows great promise, particularly with metastatic cancers. Initial phase I trials for several vectors have generated excitement over the potential power of this technique. Gene transfer is a new treatment modality that introduces new genes into a cancerous cell or the surrounding tissue to cause cell death or slow the growth of the cancer. This treatment technique is very flexible, and a wide range of genes and vectors are being used in clinical trials with successful outcomes. As these therapies mature, they may be used alone or in combination with current treatments to help make cancer a manageable disease.
| S-EPMC1570487 | biostudies-literature
Project description:Monoclonal antibodies have become a viable strategy for the delivery of therapeutic, particle emitting radionuclides specifically to tumor cells to either augment anti-tumor action of the native antibodies or to solely take advantage of their action as targeting vectors. Proper and rational selection of radionuclide and antibody combinations is critical to making radioimmunotherapy (RIT) a standard therapeutic modality due to the fundamental and significant differences in the emission of either alpha- and beta-particles. The alpha-particle has a short path length (50-80 microm) that is characterized by high linear energy transfer (100 keV microm(-1)). Actively targeted alpha-therapy potentially offers a more specific tumor cell killing action with less collateral damage to the surrounding normal tissues than beta-emitters. These properties make targeted alpha-therapy an appropriate therapy to eliminate minimal residual or micrometastatic disease. RIT using alpha-emitters such as (213)Bi, (211)At, (225)Ac, and others has demonstrated significant activity in both in vitro and in vivo model systems. Limited numbers of clinical trials have progressed to demonstrate safety, feasibility, and therapeutic activity of targeted alpha-therapy, despite having to traverse complex obstacles. Further advances may require more potent isotopes, additional sources and more efficient means of isotope production. Refinements in chelation and/or radiolabeling chemistry combined with rational improvements of isotope delivery, targeting vectors, molecular targets, and identification of appropriate clinical applications remain as active areas of research. Ultimately, randomized trials comparing targeted alpha-therapy combined with integration into existing standards of care treatment regimens will determine the clinical utility of this modality.
| S-EPMC2408446 | biostudies-literature
Project description:Neuroblastoma is the most common extracranial pediatric solid tumor with a heterogeneous clinical course, ranging from spontaneous regression to metastatic disease and death, irrespective of intensive chemotherapeutic regimen. On the basis of several parameters, children affected by neuroblastoma are stratified into low, intermediate and high risk. At present, more than 50% of high-risk patients with metastatic spread display an overall poor long-term outcome also complicated by devastating long-term morbidities. Thus, novel and more effective therapies are desperately needed to improve lifespan of high-risk patients. In this regard, adoptive cell therapy holds great promise and several clinical trials are ongoing, demonstrating safety and tolerability, with no toxicities. Starting from the immunological and clinical features of neuroblastoma, we here discuss the immunotherapeutic approaches currently adopted for high-risk patients and different innovative therapeutic strategies currently under investigation. The latter are based on the infusion of natural killer (NK) cells, as support of consolidation therapy in addition to standard treatments, or chimeric antigen receptor (CAR) T cells directed against neuroblastoma associated antigens (e.g., disialoganglioside GD2). Finally, future perspectives of adoptive cell therapies represented by ?? T lymphocyes and CAR NK cells are envisaged.
| S-EPMC7828327 | biostudies-literature
Project description:Cardiovascular diseases remain a large global health problem. Although several conventional small-molecule treatments are available for common cardiovascular problems, gene therapy is a potential treatment option for acquired and inherited cardiovascular diseases that remain with unmet clinical needs. Among potential targets for gene therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. The first approved gene therapy in the Western world was indicated for lipoprotein lipase deficiency, which causes high plasma triglyceride levels. With improved gene delivery methods and more efficient vectors, together with interventional transgene strategies aligned for a better understanding of the pathophysiology of these diseases, new approaches are currently tested for safety and efficacy in clinical trials. In this article, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.
| S-EPMC5417840 | biostudies-literature
Project description:The importance of Streptococcus pneumoniae has been well established. These bacteria can colonize infants and adults without symptoms, but in some cases can spread, invade other tissues and cause disease with high morbidity and mortality. The development of pneumococcal conjugate vaccines (PCV) caused an enormous impact in invasive pneumococcal disease and protected unvaccinated people by herd effect. However, serotype replacement is a well-known phenomenon that has occurred after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) and has also been reported for other PCVs. Therefore, it is possible that serotype replacement will continue to occur even with higher valence formulations, but the development of serotype-independent vaccines might overcome this problem. Alternative vaccines are under development in order to improve cost effectiveness, either using proteins or the pneumococcal whole cell. These approaches can be used as a stand-alone strategy or together with polysaccharide vaccines. Looking ahead, the next generation of pneumococcal vaccines can be impacted by the new technologies recently approved for human use, such as mRNA vaccines and viral vectors. In this paper, we will review the advantages and disadvantages of the addition of new polysaccharides in the current PCVs, mainly for low- and middle-income countries, and we will also address future perspectives.
| S-EPMC8620834 | biostudies-literature
Project description:Since 1928, human fetal tissues and stem cells have been used worldwide to treat various conditions. Although the transplantation of the fetal midbrain substantia nigra and dopaminergic neurons in patients suffering from Parkinson's disease is particularly noteworthy, the history of other types of grafts, such as those of the fetal liver, thymus, and pancreas, should be addressed as there are many lessons to be learnt for future stem cell transplantation. This report describes previous practices and complications that led to current clinical trials of isolated fetal stem cells and embryonic stem (ES) cells. Moreover, strategies for transplantation are considered, with a particular focus on donor cells, cell processing, and the therapeutic cell niche, in addition to ethical issues associated with fetal origin. With the advent of autologous induced pluripotent stem cells and ES cells, clinical dependence on fetal transplantation is expected to gradually decline due to lasting ethical controversies, despite landmark achievements.
| S-EPMC4172669 | biostudies-literature
Project description:Despite considerable effort and significant therapeutic advances, age-related macular degeneration (AMD) remains the commonest cause of blindness in the developed world. Progressive late-stage AMD with outer retinal degeneration currently has no proven treatment. There has been significant interest in the possibility that cellular treatments may slow or reverse visual loss in AMD. A number of modes of action have been suggested, including cell replacement and rescue, as well as immune modulation to delay the neurodegenerative process. Their appeal in this enigmatic disease relate to their generic, non-pathway-specific effects. The outer retina in particular has been at the forefront of developments in cellular regenerative therapies being surgically accessible, easily observable, as well as having a relatively simple architecture. Both the retinal pigment epithelium (RPE) and photoreceptors have been considered for replacement therapies as both sheets and cell suspensions. Studies using autologous RPE, and to a lesser extent, foetal retina, have shown proof of principle. A wide variety of cell sources have been proposed with pluripotent stem cell-derived cells currently holding the centre stage. Recent early-phase trials using these cells for RPE replacement have met safety endpoints and hinted at possible efficacy. Animal studies have confirmed the promise that photoreceptor replacement, even in a completely degenerated outer retina may restore some vision. Many challenges, however, remain, not least of which include avoiding immune rejection, ensuring long-term cellular survival and maximising effect. This review provides an overview of progress made, ongoing studies and challenges ahead.
| S-EPMC5944658 | biostudies-literature
Project description:Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.
| S-EPMC4391771 | biostudies-literature