RESUMO
Genome editing has multiple applications in the biomedical field. They can be used to modify genomes at specific locations, being able to either delete, reduce, or even enhance gene transcription and protein expression. Here, we summarize applications of genome editing used in the field of lysosomal disorders. We focus on the development of cell lines for study of disease pathogenesis, drug discovery, and pathogenicity of specific variants. Furthermore, we highlight the main studies that use gene editing as a gene therapy platform for these disorders, both in preclinical and clinical studies. We conclude that gene editing has been able to change quickly the scenario of these disorders, allowing the development of new therapies and improving the knowledge on disease pathogenesis. Should they confirm their hype, the first gene editing-based products for lysosomal disorders could be available in the next years.
Assuntos
Edição de Genes , Doenças por Armazenamento dos Lisossomos , Humanos , Terapia Genética , Genoma , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/terapia , Sistemas CRISPR-Cas/genéticaRESUMO
Sphingolipids (SLs) are lipids derived from sphingosine, and their metabolism involves a broad and complex network of reactions. Although SLs are widely distributed in the body, it is well known that they are present in high concentrations within the central nervous system (CNS). Under physiological conditions, their abundance and distribution in the CNS depend on brain development and cell type. Consequently, SLs metabolism impairment may have a significant impact on the normal CNS function, and has been associated with several disorders, including sphingolipidoses, Parkinson's, and Alzheimer's. This review summarizes the main SLs characteristics and current knowledge about synthesis, catabolism, regulatory pathways, and their role in physiological and pathological scenarios in the CNS.
Assuntos
Esfingolipidoses , Esfingolipídeos , Sistema Nervoso Central/metabolismo , Humanos , Metabolismo dos Lipídeos , Esfingolipidoses/metabolismo , Esfingolipídeos/metabolismoRESUMO
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the ß-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.
Assuntos
Proteína Ativadora de G(M2)/genética , Gangliosidoses GM2/patologia , beta-N-Acetil-Hexosaminidases/genética , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Barreira Hematoencefálica , Ensaios Clínicos como Assunto , Dieta Cetogênica , Gangliosídeo G(M2)/metabolismo , Gangliosidoses GM2/genética , Gangliosidoses GM2/metabolismo , Gangliosidoses GM2/terapia , Terapia Genética , Humanos , Mutação , Pirimetamina/uso terapêutico , Transplante de Células-TroncoRESUMO
Lysosomal storage diseases (LSDs) are a group of about 50 inborn errors of metabolism characterized by the lysosomal accumulation of partially or non-degraded molecules due to mutations in proteins involved in the degradation of macromolecules, transport, lysosomal biogenesis or modulators of lysosomal environment. Significant advances have been achieved in the diagnosis, management, and treatment of LSDs patients. In terms of approved therapies, these include enzyme replacement therapy (ERT), substrate reduction therapy, hematopoietic stem cell transplantation, and pharmacological chaperone therapy. In this review, we summarize the Colombian experience in LSDs thorough the evidence published. We identified 113 articles published between 1995 and 2019 that included Colombian researchers or physicians, and which were mainly focused in Mucopolysaccharidoses, Pompe disease, Gaucher disease, Fabry disease, and Tay-Sachs and Sandhoff diseases. Most of these articles focused on basic research, clinical cases, and mutation reports. Noteworthy, implementation of the enzyme assay in dried blood samples, led to a 5-fold increase in the identification of LSD patients, suggesting that these disorders still remain undiagnosed in the country. We consider that the information presented in this review will contribute to the knowledge of a broad spectrum of LSDs in Colombia and will also contribute to the development of public policies and the identification of research opportunities.