Clinical applications involving CNS gene transfer.
Ontology highlight
ABSTRACT:
SUBMITTER: Kantor B
PROVIDER: S-EPMC4518844 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Clinical applications involving CNS gene transfer.
Kantor Boris B McCown Thomas T Leone Paola P Gray Steven J SJ
Advances in genetics 20140101
Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood-brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying p ...[more]
Similar Datasets
Project description:Gene transfer is a widely developed technique for studying and treating genetic diseases. However, the development of therapeutic strategies is challenging, due to the cellular and functional complexity of the central nervous system (CNS), its large size and restricted access. We explored two parameters for improving gene transfer efficacy and capacity for the selective targeting of subpopulations of cells with lentiviral vectors (LVs). We first developed a second-generation LV specifically targeting astrocytes for the efficient expression or silencing of genes of interest, and to better study the importance of cell subpopulations in neurological disorders. We then made use of the retrograde transport properties of a chimeric envelope to target brain circuits affected in CNS diseases and achieve a broad distribution. The combination of retrograde transport and specific tropism displayed by this LV provides opportunities for delivering therapeutic genes to specific cell populations and ensuring high levels of transduction in interconnected brain areas following local administration. This new LV and delivery strategy should be of greater therapeutic benefit and opens up new possibilities for the preclinical development of gene therapy for neurodegenerative diseases.
| S-EPMC7902268 | biostudies-literature
Project description:Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K(+)-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K(+)-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K(+)-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms.
| S-EPMC3373146 | biostudies-literature
Project description:We report on the probable horizontal transfer of a mitochondrial gene, cytb, between species of Neotropical bruchid beetles, in a zone where these species are sympatric. The bruchid beetles Acanthoscelides obtectus, A. obvelatus, A. argillaceus and Zabrotes subfasciatus develop on various bean species in Mexico. Whereas A. obtectus and A. obvelatus develop on Phaseolus vulgaris in the Mexican Altiplano, A. argillaceus feeds on P. lunatus in the Pacific coast. The generalist Z. subfasciatus feeds on both bean species, and is sympatric with A. obtectus and A. obvelatus in the Mexican Altiplano, and with A. argillaceus in the Pacific coast. In order to assess the phylogenetic position of these four species, we amplified and sequenced one nuclear (28S rRNA) and two mitochondrial (cytb, COI) genes.Whereas species were well segregated in topologies obtained for COI and 28S rRNA, an unexpected pattern was obtained in the cytb phylogenetic tree. In this tree, individuals from A. obtectus and A. obvelatus, as well as Z. subfasciatus individuals from the Mexican Altiplano, clustered together in a unique little variable monophyletic unit. In contrast, A. argillaceus and Z. subfasciatus individuals from the Pacific coast clustered in two separated clades, identically to the pattern obtained for COI and 28S rRNA. An additional analysis showed that Z. subfasciatus individuals from the Mexican Altiplano also possessed the cytb gene present in individuals of this species from the Pacific coast. Zabrotes subfasciatus individuals from the Mexican Altiplano thus demonstrated two cytb genes, an "original" one and an "infectious" one, showing 25% of nucleotide divergence. The "infectious" cytb gene seems to be under purifying selection and to be expressed in mitochondria.The high degree of incongruence of the cytb tree with patterns for other genes is discussed in the light of three hypotheses: experimental contamination, hybridization, and pseudogenisation. However, none of these seem able to explain the patterns observed. A fourth hypothesis, involving recent horizontal gene transfer (HGT) between A. obtectus and A. obvelatus, and from one of these species to Z. subfasciatus in the Mexican Altiplano, seems the only plausible explanation. The HGT between our study species seems to have occurred recently, and only in a zone where the three beetles are sympatric and share common host plants. This suggests that transfer could have been effected by some external vector such as a eukaryotic or viral parasite, which might still host the transferred fragment.This article was reviewed by Eric Bapteste, Adam Eyre-Walker and Alexey Kondrashov.
| S-EPMC1562361 | biostudies-literature
Project description:BackgroundFaecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication.AimTo provide an expert consensus on current clinical indications, applications and methodological aspects of FMT.MethodsWell-acknowledged experts from various countries in Europe have contributed to this article. After literature review, consensus has been achieved by repetitive circulation of the statements and the full manuscript among all authors with intermittent adaptation to comments (using a modified Delphi process). Levels of evidence and agreement were rated according to the GRADE system. Consensus was defined a priori as agreement by at least 75% of the authors.ResultsKey recommendations include the use of FMT in recurrent C. difficile infection characterised by at least two previous standard treatments without persistent cure, as well as its consideration in severe and severe-complicated C. difficile infection as an alternative to total colectomy in case of early failure of antimicrobial therapy. FMT in inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and metabolic syndrome should only be performed in research settings.ConclusionsFaecal microbiota transplantation or transfer is a promising treatment for a variety of diseases in which the intestinal microbiota is disturbed. For indications other than C. difficile infection, more evidence is needed before more concrete recommendations can be made.
| S-EPMC6680358 | biostudies-literature
Project description:BACKGROUND:The revolutionary concept of "jumping genes" was conceived by McClintock in the late 1940s while studying the Activator/Dissociation (Ac/Ds) system in maize. Transposable elements (TEs) represent the most abundant component of many eukaryotic genomes. Mobile elements are a driving force of eukaryotic genome evolution. McClintock's Ac, the autonomous element of the Ac/Ds system, together with hobo from Drosophila and Tam3 from snapdragon define an ancient and diverse DNA transposon superfamily named hAT. Other members of the hAT superfamily include the insect element Hermes and Tol2 from medaka. In recent years, genetic tools derived from the 'cut' and 'paste' Tol2 DNA transposon have been widely used for genomic manipulation in zebrafish, mammals and in cells in vitro. RESULTS:We report the purification of a functional recombinant Tol2 protein from E.coli. We demonstrate here that following microinjection using a zebrafish embryo test system, purified Tol2 transposase protein readily catalyzes gene transfer in both somatic and germline tissues in vivo. We show that purified Tol2 transposase can promote both in vitro cutting and pasting in a defined system lacking other cellular factors. Notably, our analysis of Tol2 transposition in vitro reveals that the target site preference observed for Tol2 in complex host genomes is maintained using a simpler target plasmid test system, indicating that the primary sequence might encode intrinsic cues for transposon integration. CONCLUSIONS:This active Tol2 protein is an important new tool for diverse applications including gene discovery and molecular medicine, as well as for the biochemical analysis of transposition and regulation of hAT transposon/genome interactions. The measurable but comparatively modest insertion site selection bias noted for Tol2 is largely determined by the primary sequence encoded in the target sequence as assessed through studying Tol2 protein-mediated transposition in a cell-free system.
| S-EPMC4818426 | biostudies-literature
Project description:Retinal degenerative diseases are a major cause of blindness. Retinal gene therapy is a trail-blazer in the human gene therapy field, leading to the first FDA approved gene therapy product for a human genetic disease. The application of Clustered Regularly Interspaced Short Palindromic Repeat/Cas9 (CRISPR/Cas9)-mediated gene editing technology is transforming the delivery of gene therapy. We review the history, present, and future prospects of retinal gene therapy.
| S-EPMC8982485 | biostudies-literature
Project description:Nonviral nanoparticles have emerged as an attractive alternative to viral vectors for gene therapy applications, utilizing a range of lipid-based, polymeric, and inorganic materials. These materials can either encapsulate or be functionalized to bind nucleic acids and protect them from degradation. To effectively elicit changes to gene expression, the nanoparticle carrier needs to undergo a series of steps intracellularly, from interacting with the cellular membrane to facilitate cellular uptake to endosomal escape and nucleic acid release. Adjusting physiochemical properties of the nanoparticles, such as size, charge, and targeting ligands, can improve cellular uptake and ultimately gene delivery. Applications in the central nervous system (CNS; i.e., neurological diseases, brain cancers) face further extracellular barriers for a gene-carrying nanoparticle to surpass, with the most significant being the blood-brain barrier (BBB). Approaches to overcome these extracellular challenges to deliver nanoparticles into the CNS include systemic, intracerebroventricular, intrathecal, and intranasal administration. This review describes and compares different biomaterials for nonviral nanoparticle-mediated gene therapy to the CNS and explores challenges and recent preclinical and clinical developments in overcoming barriers to nanoparticle-mediated delivery to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
| S-EPMC10023321 | biostudies-literature
Project description:Insect-derived baculoviruses have emerged as versatile and safe workhorses of biotechnology. Baculovirus expression vectors (BEVs) have been applied widely for crop and forest protection, as well as safe tools for recombinant protein production in insect cells. However, BEVs ability to efficiently transduce noninsect cells is still relatively poorly recognized despite the fact that efficient baculovirus-mediated in vitro and ex vivo gene delivery into dormant and dividing vertebrate cells of diverse origin has been described convincingly by many authors. Preliminary proof of therapeutic potential has also been established in preclinical studies. This review summarizes the advantages and current status of baculovirus-mediated gene delivery. Stem cell transduction, preclinical animal studies, tissue engineering, vaccination, cancer gene therapy, viral vector production, and drug discovery are covered.
| S-EPMC3616530 | biostudies-other
Project description:There are over 70 known lysosomal storage disorders (LSDs), most caused by mutations in genes encoding lysosomal hydrolases. Central nervous system involvement is a hallmark of the majority of LSDs and, if present, generally determines the prognosis of the disease. Nonetheless, brain disease is currently poorly targeted by available therapies, including systemic enzyme replacement therapy, mostly (but not only) due to the presence of the blood-brain barrier that restricts the access of orally or parenterally administered large molecules into the brain. Thus, one of the greatest and most exciting challenges over coming years will be to succeed in developing effective therapies for the treatment of central nervous system manifestations in LSDs. Over recent years, gene therapy (GT) has emerged as a promising therapeutic strategy for a variety of inherited neurodegenerative diseases. In LSDs, the ability of genetically corrected cells to cross-correct adjacent lysosomal enzyme-deficient cells in the brain after gene transfer might enhance the diffusion of the recombinant enzyme, making this group of diseases a strong candidate for such an approach. Both in vivo (using the administration of recombinant adeno-associated viral vectors) and ex vivo (auto-transplantation of lentiviral vector-modified hematopoietic stem cells-HSCs) strategies are feasible. Promising results have been obtained in an ever-increasing number of preclinical studies in rodents and large animal models of LSDs, and these give great hope of GT successfully correcting neurological defects, once translated to clinical practice. We are now at the stage of treating patients, and various clinical trials are underway, to assess the safety and efficacy of in vivo and ex vivo GT in several neuropathic LSDs. In this review, we summarize different approaches being developed and review the current clinical trials related to neuropathic LSDs, their results (if any), and their limitations. We will also discuss the pitfalls and the remaining challenges.
| S-EPMC8481654 | biostudies-literature
Project description:Primary immunodeficiencies (PIDs) have represented a paradigmatic model for successes and pitfalls of hematopoietic stem cells gene therapy. First clinical trials performed with gamma retroviral vectors (?-RV) for adenosine deaminase severe combined immunodeficiency (ADA-SCID), X-linked SCID (SCID-X1), and Wiskott-Aldrich syndrome (WAS) showed that gene therapy is a valid therapeutic option in patients lacking an HLA-identical donor. No insertional mutagenesis events have been observed in more than 40 ADA-SCID patients treated so far in the context of different clinical trials worldwide, suggesting a favorable risk-benefit ratio for this disease. On the other hand, the occurrence of insertional oncogenesis in SCID-X1, WAS, and chronic granulomatous disease (CGD) RV clinical trials prompted the development of safer vector construct based on self-inactivating (SIN) retroviral or lentiviral vectors (LVs). Here we present the recent results of LV-mediated gene therapy for WAS showing stable multilineage engraftment leading to hematological and immunological improvement, and discuss the differences with respect to the WAS RV trial. We also describe recent clinical results of SCID-X1 gene therapy with SIN ?-RV and the perspectives of targeted genome editing techniques, following early preclinical studies showing promising results in terms of specificity of gene correction. Finally, we provide an overview of the gene therapy approaches for other PIDs and discuss its prospects in relation to the evolving arena of allogeneic transplant.
| S-EPMC4410188 | biostudies-literature