Abstract:
:The ultimate goal of muscular dystrophy gene therapy is to treat all muscles in the body. Global gene delivery was demonstrated in dystrophic mice more than a decade ago using adeno-associated virus (AAV). However, translation to affected large mammals has been challenging. The only reported attempt was performed in newborn Duchenne muscular dystrophy (DMD) dogs. Unfortunately, AAV injection resulted in growth delay, muscle atrophy and contracture. Here we report safe and bodywide AAV delivery in juvenile DMD dogs. Three ∼2-m-old affected dogs received intravenous injection of a tyrosine-engineered AAV-9 reporter or micro-dystrophin (μDys) vector at the doses of 1.92-6.24 × 10(14) viral genome particles/kg under transient or sustained immune suppression. DMD dogs tolerated injection well and their growth was not altered. Hematology and blood biochemistry were unremarkable. No adverse reactions were observed. Widespread muscle transduction was seen in skeletal muscle, the diaphragm and heart for at least 4 months (the end of the study). Nominal expression was detected in internal organs. Improvement in muscle histology was observed in μDys-treated dogs. In summary, systemic AAV gene transfer is safe and efficient in young adult dystrophic large mammals. This may translate to bodywide gene therapy in pediatric patients in the future.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Yue Y,Pan X,Hakim CH,Kodippili K,Zhang K,Shin JH,Yang HT,McDonald T,Duan Ddoi
10.1093/hmg/ddv310subject
Has Abstractpub_date
2015-10-15 00:00:00pages
5880-90issue
20eissn
0964-6906issn
1460-2083pii
ddv310journal_volume
24pub_type
杂志文章abstract::Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy021
更新日期:2018-04-01 00:00:00
abstract::5-Methylcytosine (5mC), generated through the covalent addition of a methyl group to the fifth carbon of cytosine, is the most prevalent DNA modification in humans and functions as a critical player in the regulation of tissue and cell-specific gene expression. 5mC can be oxidized to 5-hydroxymethylcytosine (5hmC) by ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz273
更新日期:2020-01-01 00:00:00
abstract::The Pearson marrow-pancreas syndrome (MIM 557000) is a disorder involving the hematopoietic system and the exocrine pancreas in early infancy. We have previously shown that this disease results from a defect of oxidative phosphorylation associated with deletions of the mitochondrial DNA. We present here a series of 21...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.8.1327
更新日期:1995-08-01 00:00:00
abstract::Huntington's disease (HD) is caused by expansion of a glutamine repeat in huntingtin. Mutant huntingtin contains 36-55 repeats in adult HD patients and >60 repeats in juvenile HD patients. An N-terminal fragment of mutant huntingtin forms aggregates in neuronal nuclei in the brains of transgenic mice and HD patients. ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.5.777
更新日期:1998-05-01 00:00:00
abstract::The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating thr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn235
更新日期:2008-11-01 00:00:00
abstract::Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein-coding potential is the detection of cellular protein expression through peptide mass spectrometry (MS) experiments. Here, we mapped peptides detected in seven large-scale prote...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu309
更新日期:2014-11-15 00:00:00
abstract::Bone mineral density (BMD) is one of the major determinants of risk for osteoporotic fracture. Multiple studies reveal that peak bone mass is under strong genetic influence. One of the major susceptibility loci for peak spine BMD has been mapped to chromosome 1q21-q23 in the Caucasian population. We have previously re...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn397
更新日期:2009-02-15 00:00:00
abstract::A cluster of imprinted genes on human chromosome 15q11-q13 (the PWS/AS domain) and its ortholog on mouse chromosome 7c is believed to be regulated by an imprinting control center. Although minideletions in this region in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) patients revealed that two elements, shorte...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh085
更新日期:2004-04-01 00:00:00
abstract::Using a bromodeoxyuridine incorporation method to detect replicated DNA, we studied allele-specific replication of several sites within the human Prader-Willi/Angelman and IGF2/H19 imprinted regions. No obvious allele-specific differences in time of replication were detected at most loci previously reported to replica...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2287
更新日期:1995-12-01 00:00:00
abstract::Deficiency of the mitochondrial matrix protein frataxin causes Friedreich ataxia. Frataxin function is believed to be related to mitochondrial iron metabolism and free radical production. In Friedreich ataxia, loss of dorsal root ganglia neurons occurs early in life, suggesting a developmental process. In addition, fr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.18.1935
更新日期:2001-09-01 00:00:00
abstract::Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterati...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr381
更新日期:2011-12-01 00:00:00
abstract::X-linked juvenile retinoschisis (XLRS) is an early-onset inherited condition that affects primarily males and is characterized by cystic lesions of the inner retina, decreased visual acuity and contrast sensitivity and a selective reduction of the electroretinogram (ERG) b-wave. Although XLRS is genetically heterogene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz122
更新日期:2019-09-15 00:00:00
abstract::The term 'dynamic mutation' was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation. The past decade has seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized 'rare' ch...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/10.20.2187
更新日期:2001-10-01 00:00:00
abstract::We describe a method for rapid identification of chromosomes at metaphase, and quantification of chromosomes in interphase, by annealing oligonucleotide primers, derived from chromosome-specific subsets of repeated DNA families, to the DNA of cytological preparations, and enzymatic extension with the incorporation of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.6.931
更新日期:1994-06-01 00:00:00
abstract::Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mell...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi453
更新日期:2006-01-15 00:00:00
abstract::Nineteen Wnt ligands and 10 Frizzled (Fz) receptors mediate multiple distinct cellular events during neuronal development. However, their precise roles in cell-type specification and organogenesis are poorly delineated because of overlapping functions and expression profiles. Here, we have explored the role of two clo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr616
更新日期:2012-04-15 00:00:00
abstract::Myotonic dystrophy type I (DM1) is an RNA-mediated disease caused by a non-coding CTG repeat expansion. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. A link has been established between splicing regulation by CUG-BP1, a member of the CELF family of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi162
更新日期:2005-06-01 00:00:00
abstract::Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.7.1117
更新日期:1994-07-01 00:00:00
abstract::What would define real progress in the field of deafness research in fundamental and medical terms? In fundamental terms, progress would be measured by an improvement in our knowledge of the development and physiology of the ear. In medical terms, progress would lead to the division of the broad category of hearing de...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/7.10.1589
更新日期:1998-01-01 00:00:00
abstract::Fragile X syndrome, the most common form of inherited mental retardation, is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a ubiquitously expressed, multi-domain RNA-binding protein, but its in vivo function remains poorly understood. Recent studies have shown that FMRP participates in...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds307
更新日期:2012-11-01 00:00:00
abstract::'Pure' familial spastic paraplegias (FSP) are neurodegenerative disorders that are clinically characterized by progressive spasticity of the lower limbs and are inherited as autosomal dominant (DFSP) or autosomal recessive (RFSP) traits. The primary defect in FSP is unknown. Genetic linkage analysis was applied to fiv...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.8.1263
更新日期:1994-08-01 00:00:00
abstract::The Menkes disease gene encodes a P-type transmembrane ATPase (ATP7A) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway. ATP7A moves from the trans-Golgi network (TGN) to the cell surface in response to exogenously added copper ions and recycles back to ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg166
更新日期:2003-07-01 00:00:00
abstract::The purpose of this study was to determine whether thrombospondin (TSP)-1 promotes macrophage activity and disease progression in dysferlinopathy. First, we found that levels of TSP-1 are elevated in blood of non-ambulant dysferlinopathy patients compared with ambulant patients and healthy controls, supporting the ide...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx378
更新日期:2017-12-15 00:00:00
abstract::KDM6B/JMJD3 is a histone H3 lysine demethylase with an important gene regulatory role in development and physiology. Here, we show that human JMJD3 expression is induced by the active vitamin D metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and that JMJD3 modulates the gene regulatory action of this hormone....
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr399
更新日期:2011-12-01 00:00:00
abstract::Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone diseas...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx178
更新日期:2017-08-15 00:00:00
abstract::Lung cancer is the leading cause of cancer death in North America. Despite advances in lung cancer treatment, the overall 5 year survival rate for those diagnosed with the disease is bleak presumably due to the late stage of diagnosis. Owing to the difficulty of early detection, preneoplastic specimens are rare. Howev...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi043
更新日期:2005-02-15 00:00:00
abstract::The internal structure of different alleles of the minisatellite present at the 3' end of the apolipoprotein B (ApoB) gene has been analysed by different approaches including sequencing. The repeat unit arrangements of the minisatellite on 570 chromosomes belonging to European and African populations were thus determi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.1.61
更新日期:1996-01-01 00:00:00
abstract::Galphaq, encoded by the human GNAQ gene, is an effector subunit of the Gq heterotrimeric G-protein and the convergence point for signaling of multiple Gq-coupled neurohormonal receptors. To identify naturally occurring mutations that could modify GNAQ transcription, we examined genomic DNA isolated from 355 normal sub...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm229
更新日期:2007-11-15 00:00:00
abstract::Mutations in Alsin are associated with chronic juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. The primary pathology and pathogenic mechanism of the disease remain largely unknown. Here we show that alsin-deficient mice have motor impai...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm251
更新日期:2007-12-01 00:00:00
abstract::Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/- and Tsc2+/- mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp149
更新日期:2009-06-15 00:00:00