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1.
Hum Gene Ther ; 34(9-10): 404-415, 2023 05.
Article in English | MEDLINE | ID: mdl-36694468

ABSTRACT

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened, yet, functional microdystrophin genes has emerged as a promising treatment. This article seeks to explain the rationale for use of the accelerated approval pathway to advance AAV microdystrophin gene therapy for DMD. Specifically, we provide support for the use of microdystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.


Subject(s)
Muscular Dystrophy, Duchenne , Male , Humans , Muscular Dystrophy, Duchenne/genetics , Muscle, Skeletal/metabolism , Genetic Therapy/methods , Gene Transfer Techniques , Biomarkers/metabolism
3.
Nat Rev Drug Discov ; 16(8): 513-514, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28496147

ABSTRACT

New opportunities to develop innovative - and often complex - products that combine drugs, devices and/or biological components are rapidly emerging, raising questions about how such products should be regulated. Here, we discuss the ongoing efforts of the FDA to develop a modern, transparent, flexible and consistent science-based regulatory approach for combination products.


Subject(s)
Device Approval/legislation & jurisprudence , Drug Approval/legislation & jurisprudence , Drug and Narcotic Control , Medical Device Legislation , Drug Design , Equipment Design , Humans , United States , United States Food and Drug Administration
4.
Nat Rev Drug Discov ; 16(5): 297-298, 2017 May.
Article in English | MEDLINE | ID: mdl-28232726

ABSTRACT

Growing access to diverse 'real-world' data sources is enabling new approaches to close persistent evidence gaps about the optimal use of medical products in real-world practice. Here, we argue that contrary to widespread impressions, existing FDA regulations embody sufficient flexibility to accommodate the emerging tools and methods needed to achieve this goal.


Subject(s)
Clinical Trials as Topic/methods , Drug Design , Drug and Narcotic Control , United States Food and Drug Administration/legislation & jurisprudence , Humans , Time Factors , United States
7.
Development ; 134(19): 3449-60, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17728348

ABSTRACT

Both hindbrain roof plate epithelium (hRPe) and hindbrain choroid plexus epithelium (hCPe) produce morphogens and growth factors essential for proper hindbrain development. Despite their importance, little is known about how these essential structures develop. Recent genetic fate maps indicate that hRPe and hCPe descend from the same pool of dorsal neuroectodermal progenitor cells of the rhombic lip. A linear developmental progression has been assumed, with the rhombic lip producing non-mitotic hRPe, and seemingly uniform hRPe transforming into hCPe. Here, we show that hRPe is not uniform but rather comprises three spatiotemporal fields, which differ in organization, proliferative state, order of emergence from the rhombic lip, and molecular profile of either the constituent hRPe cells themselves and/or their parental progenitors. Only two fields contribute to hCPe. We also present evidence for an hCPe contribution directly by the rhombic lip at late embryonic stages when hRPe is no longer present; indeed, the production interval for hCPe by the rhombic lip is surprisingly extensive. Further, we show that the hCPe lineage appears to be unique among the varied rhombic lip-derived lineages in its proliferative response to constitutively active Notch1 signaling. Collectively, these findings provide a new platform for investigating hRPe and hCPe as neural organizing centers and provide support for the model that they are themselves patterned structures that might be capable of influencing neural development along multiple spatial and temporal axes.


Subject(s)
Choroid Plexus/embryology , Rhombencephalon/embryology , Animals , Body Patterning , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/physiology , Choroid Plexus/metabolism , Epithelium/embryology , Epithelium/metabolism , Gene Expression Regulation, Developmental , Growth Differentiation Factors , Mice , Mice, Transgenic , Models, Neurological , Receptor, Notch1/genetics , Receptor, Notch1/physiology , Rhombencephalon/metabolism , Signal Transduction
8.
Dev Dyn ; 235(1): 279-84, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16278878

ABSTRACT

Frodo has been identified as a protein interacting with Dishevelled, an essential mediator of the Wnt signaling pathway, critical for the determination of cell fate and polarity in embryonic development. In this study, we use specific gene probes to characterize stage- and tissue-specific expression patterns of the mouse Frodo homologue and compare them with Frodo expression patterns in Xenopus embryos. In situ hybridization analysis of mouse Frodo transcripts demonstrates that, similar to Xenopus Frodo, mouse Frodo is expressed in primitive streak mesoderm, neuroectoderm, neural crest, presomitic mesoderm, and somites. In many cases, Frodo expression is confined to tissues undergoing extensive morphogenesis, suggesting that Frodo may be involved in the regulation of cell shape and motility. Highly conserved dynamic expression patterns of Frodo homologues indicate a similar function for these proteins in different vertebrates.


Subject(s)
Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Cell Movement/physiology , Embryonic Development/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Morphogenesis/genetics , Structural Homology, Protein , Xenopus Proteins/genetics , Adaptor Proteins, Signal Transducing , Animals , Cell Shape/genetics , Embryo, Nonmammalian/metabolism , Mice , Mice, Inbred ICR , Molecular Sequence Data , RNA-Binding Proteins , Xenopus Proteins/biosynthesis
9.
Neuron ; 48(6): 933-47, 2005 Dec 22.
Article in English | MEDLINE | ID: mdl-16364898

ABSTRACT

The lower rhombic lip (LRL) is a germinal zone in the dorsal hindbrain productive of tangentially migrating neurons, streaming extramurally (mossy fiber neurons) or intramurally (climbing fiber neurons). Here we show that LRL territory, operationally defined by Wnt1 expression, is parceled into molecular subdomains predictive of cell fate. Progressing dorsoventrally, Lmx1a and Gdf7 expression identifies the primordium for hindbrain choroid plexus epithelial cells; Math1, for mossy fiber neurons; and immediately ventral to Math1 yet within Wnt1(+) territory, a climbing fiber primordium dominated by Ngn1-expressing cells. Elimination of Pax6 results in expansion of this Ngn1(+) progenitor pool and reduction in the Math1(+) pool, with accompanying later enlargement of the climbing fiber nucleus and reductions in mossy fiber nuclei. Pax6 loss also disrupts Msx expression cell-nonautonomously, suggesting Pax6 may influence LRL progenitor identity indirectly through potentiating BMP signaling. These studies suggest that underlying the diversity and proportions of fates produced by the LRL is a precise suborganization regulated by Pax6.


Subject(s)
Afferent Pathways/embryology , Cerebellum/embryology , Eye Proteins/metabolism , Homeodomain Proteins/metabolism , Nerve Fibers/metabolism , Paired Box Transcription Factors/metabolism , Repressor Proteins/metabolism , Rhombencephalon/embryology , Stem Cells/metabolism , Afferent Pathways/cytology , Afferent Pathways/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Body Patterning/genetics , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/metabolism , Cell Differentiation/genetics , Cell Movement/genetics , Cerebellum/cytology , Cerebellum/metabolism , Choroid Plexus/cytology , Choroid Plexus/embryology , Choroid Plexus/metabolism , Eye Proteins/genetics , Gene Expression Regulation, Developmental/genetics , Growth Differentiation Factors , Homeodomain Proteins/genetics , LIM-Homeodomain Proteins , Mice , Mice, Transgenic , Nerve Fibers/ultrastructure , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Olivary Nucleus/cytology , Olivary Nucleus/embryology , Olivary Nucleus/metabolism , PAX6 Transcription Factor , Paired Box Transcription Factors/genetics , Repressor Proteins/genetics , Rhombencephalon/cytology , Rhombencephalon/metabolism , Stem Cells/cytology , Transcription Factors , Wnt1 Protein/genetics , Wnt1 Protein/metabolism
10.
Genesis ; 41(3): 99-109, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15729687

ABSTRACT

The selectivity by which site-specific recombinase-mediated genetic changes can be targeted to specific cells in the mouse has been limited by the fact that many genes used as recombinase "drivers" are expressed either in cell populations that change over time or constitutively in a given cell population for an extended time period, for example, in a germinal zone that gives rise successively to different lineages. These scenarios limit the selective dimension of conditional gene modification experiments as they preclude studying the later-generated lineages either because of earlier phenotypes (in the case of conditional mutagenesis experiments) or because the early and permanent activation of a reporter in a germinal zone results in all descendant lineages being marked (in the case of fate-mapping experiments). To circumvent this limitation, inducible forms of Cre recombinase have been developed, enabling the induction of genetic changes in late embryonic or adult cells accessible only through late aspects of a dynamic driver gene expression profile. To increase the number of tools available for engineering genetic changes in selective cell populations, we have generated a ligand-regulated form of Flpe using the recombinase-steroid receptor fusion approach. In two prototypical scenarios, we show that the fused gene product, FlpeER(T2), is competent to mediate DNA recombination in vivo and responds specifically to the inducer tamoxifen in a dose-dependent manner without detectable background activity.


Subject(s)
DNA Nucleotidyltransferases/genetics , DNA Nucleotidyltransferases/metabolism , Genetic Engineering/methods , Receptors, Estrogen/genetics , Animals , Binding Sites , DNA, Recombinant , Enzyme Activation , Gene Expression Regulation, Developmental/drug effects , Genes, Reporter , Ligands , Mice , Mice, Transgenic , Protein Structure, Tertiary , Receptors, Estrogen/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/pharmacology , Time Factors , Transgenes
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