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1.发明授权Method for aiding in the diagnosis of in-frame deletion type congenital muscular dystrophy 失效帮助诊断框内缺失型先天性肌营养不良症的方法
公开(公告)号：US6136546A
公开(公告)日：2000-10-24
申请号：US57740
申请日：1998-04-09
IPC分类号： G01N33/68 , G01N33/53 , G01N1/30 , G01N33/567
CPC分类号： G01N33/6887 , G01N2800/2878
摘要： Disclosed are compositions and methods for aiding in the diagnosis of congenital muscular dystrophy associated with in-frame deletion in the laminin-2 .alpha.2 polypeptide chain in an individual. In a preferred diagnostic method embodiment, an experimental muscle tissue sample is provided from the individual and treated if necessary to render components available for antibody binding. The components of the sample are then separated on the basis of molecular weight. The separated protein components are then transferred to a solid support while maintaining the relative positions established in separation step. The transferred components are then stained with an affinity reagent which is known to bind to a C-terminal domain of the laminin-2 .alpha.2 polypeptide chain. Individual afflicted with congenital muscular dystrophy associated with in-frame deletion in the laminin-2 .alpha.2 polypeptide chain on the basis of positive staining in combination with reduced molecular weight of the laminin-2 .alpha.2 polypeptide chain relative to the wild-type laminin-2 .alpha.2 polypeptide chain. A preferred composition is a nucleic acid probe for the detection of merosin deletion-type congenital muscular dystrophy. The preferred nucleic acid probe is characterized by the ability to bind specifically to a mutant merosin nucleic acid sequence, the mutant merosin nucleic acid sequence comprising a T to C substitution at position 3973 +2 of the consensus donor splice site of exon 25.
摘要翻译： 公开了用于帮助诊断个体中层粘连蛋白-2α2多肽链中与框内缺失相关的先天性肌营养不良的组合物和方法。 在优选的诊断方法实施方案中，从个体提供实验肌肉组织样品，并且如果需要进行处理以使组分可用于抗体结合。 然后基于分子量分离样品的组分。 然后将分离的蛋白质组分转移到固体支持物中，同时保持在分离步骤中建立的相对位置。 转移的组分然后用已知结合层粘连蛋白-2α2多肽链的C末端结构域的亲和试剂染色。 基于阳性染色结合层粘连蛋白-2α2多肽链相对于野生型层粘连蛋白的层粘连蛋白-2α2多肽链的分子量降低而与层粘连蛋白-2α2多肽链中的框内缺失相关的先天性肌营养不良患者， 2α2多肽链。 优选的组合物是用于检测梅洛辛缺失型先天性肌营养不良症的核酸探针。 优选的核酸探针的特征在于特异性结合突变型子糖蛋白核酸序列的能力，所述突变蛋清核酸序列包含外显子25的共有供体剪接位点的第3973±2位的T至C取代。
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公开(公告)号：US5672694A
公开(公告)日：1997-09-30
申请号：US547182
申请日：1995-10-24
申请人： Kevin P. Campbell , Leland Lim , Franck Duclos , Yoshihide Sunada , Jacques S. Beckmann , Odile Broux , Fernando M. S. Tome , Michel Fardeau , Charles E. Jackson
发明人： Kevin P. Campbell , Leland Lim , Franck Duclos , Yoshihide Sunada , Jacques S. Beckmann , Odile Broux , Fernando M. S. Tome , Michel Fardeau , Charles E. Jackson
CPC分类号： C07K14/4707 , C12Q1/6883 , A61K39/00 , C12Q2600/156 , C12Q2600/172
摘要： Disclosed herein is a substantially pure nucleic acid sequence encoding a mammalian 43 kDa non-dystrophin component (.beta.-sarcoglycan) of the dystrophin-glycoprotein complex. Also disclosed are immunogenic peptides which, when used to immunize a mammal, stimulate the production of antibodies which bind specifically to the .beta.-sarcoglycan. Mutations in the .beta.-sarcoglycan gene which are associated with autosomal recessive limb-girdle muscular dystrophy are also disclosed. The identification of such mutations enables the design of nucleic acid probes which hybridize specifically to a mutant form of .beta.-sarcoglycan, or the complement thereof, but not to the DNA of the wild-type form of the gene (or the complement thereof), under stringent hybridization conditions. Such probes are useful, for example, in connection with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. In addition, the identification of such mutations enables the diagnosis of autosomal recessive limb-girdle muscular dystrophy through the use of direct DNA sequencing techniques.
摘要翻译： 本文公开了编码肌营养不良蛋白 - 糖蛋白复合物的哺乳动物43kDa非肌营养不良蛋白成分（β-卡非糖）的基本上纯的核酸序列。 还公开了免疫原性肽，其当用于免疫哺乳动物时，刺激特异性结合β-糖聚糖的抗体的产生。 还公开了与常染色体隐性遗传性肢体肌营养不良症相关的β - 肌凝蛋白基因的突变。 这种突变的鉴定使得能够设计与β-丝裂核糖苷或其补体的突变形式特异性杂交的核酸探针，而不与野生型形式的基因（或其补体）的DNA杂交， 在严格的杂交条件下。 这样的探针可用于例如与常染色体隐性性腰带肌营养不良症的诊断有关。 此外，通过使用直接DNA测序技术，鉴定这种突变能够诊断常染色体隐性的腰带肌营养不良症。
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公开(公告)号：US5733732A
公开(公告)日：1998-03-31
申请号：US582539
申请日：1996-01-03
申请人： Kevin P. Campbell , Steven L. Roberds , Yoshihide Sunada , Federica Piccolo , Marc Jeanpierre , Jean-Claude Kaplan
发明人： Kevin P. Campbell , Steven L. Roberds , Yoshihide Sunada , Federica Piccolo , Marc Jeanpierre , Jean-Claude Kaplan
CPC分类号： C12Q1/6883 , C12Q2600/156
摘要： Disclosed herein are compositions and methods for the detection of primary adhalinopathy. More specifically, disclosed herein are nucleic acid probes which hybridize specifically, under stringent hybridization conditions, to a mutant adhalin gene or the complement thereof, but not to the corresponding region of a wild-type adhalin gene. Also disclosed are methods for the detection of a mutation in the human adhalin gene which is responsible for primary adhalinopathy. Such methods include the use of the nucleic acid probes of the invention for detection of the myopathy by hybridization, as well as detection by direct DNA sequencing techniques.
摘要翻译： 本文公开了用于检测原发性腺瘤病的组合物和方法。 更具体地，本文公开了在严格杂交条件下特异性与突变体阿达肝素基因或其互补序列而不是野生型腺恶素基因的相应区域杂交的核酸探针。 还公开了用于检测负责原代腺病变的人腺酸基因突变的方法。 这些方法包括使用本发明的核酸探针通过杂交检测肌病，以及通过直接DNA测序技术的检测。
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公开(公告)号：US5863743A
公开(公告)日：1999-01-26
申请号：US289668
申请日：1994-08-12
CPC分类号： G01N33/6887 , G01N2333/4712 , G01N2800/2878 , Y10S435/96 , Y10S436/811
摘要： Disclosed is a method for aiding in the diagnosis of merosin deficiency-type congenital muscular dystrophy (CMD). The method is based on the discovery of a previously unidentified form of CMD which is characterized by a substantial reduction in the levels of merosin in skeletal muscle tissue containing normal levels of dystrophin and dystrophin-associated proteins.
摘要翻译： 公开了一种帮助诊断梅洛辛缺乏型先天性肌营养不良症（CMD）的方法。 该方法基于以前未鉴定形式的CMD的发现，其特征在于含有正常水平的肌营养不良蛋白和肌营养不良蛋白相关蛋白的骨骼肌组织中肌糖蛋白水平的显着降低。
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公开(公告)号：US06211340B1
公开(公告)日：2001-04-03
申请号：US09119827
申请日：1998-07-21
申请人： Kevin P. Campbell , Daniel Jung , Franck Duclos , Volker Straub , John McPherson
发明人： Kevin P. Campbell , Daniel Jung , Franck Duclos , Volker Straub , John McPherson
IPC分类号： C07K1618
CPC分类号： C07K14/4707
摘要： Disclosed herein is a substantially pure nucleic acid sequence encoding a mammalian 35 kDa non-dystrophin component (&dgr;-sarcoglycan) of the dystrophin-glycoprotein complex. Also disclosed are the amino acid sequence and an immunogenic peptide of &dgr;-sarcoglycan. The peptide when used to immunize a mammal, stimulates the production of antibodies which bind specifically to the &dgr;-sarcoglycan. Methods to identify mutations in the &dgr;-sarcoglycan gene associated with autosomal recessive limb-girdle muscular dystrophy are also disclosed. The identification of such mutations enables the design of nucleic acid probes which hybridize specifically to a mutant form of &dgr;-sarcoglycan, or the complement thereof, but not to the DNA of the wild-type form of the gene (or the complement thereof), under stringent hybridization conditions. Such probes are useful, for example, in connection with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. In addition, the identification of such mutations enables the diagnosis of autosomal recessive limb-girdle muscular dystrophy through the use of direct DNA sequencing techniques.
摘要翻译： 本文公开了编码肌营养不良蛋白 - 糖蛋白复合物的哺乳动物35kDa非肌营养不良蛋白成分（δ-莽草酸）的基本上纯的核酸序列。 还公开了δ-色氨酸的氨基酸序列和免疫原性肽。 当肽用于免疫哺乳动物时，刺激产生与δ-糖聚糖特异性结合的抗体。 还公开了鉴定与常染色体隐性遗传性肢体肌营养不良症相关的δ-色氨酸聚糖基因突变的方法。 这种突变的鉴定使得能够设计特异性地与δ-色氨酸聚糖或其互补体的突变形式杂交的核酸探针，而不与野生型形式的基因（或其互补物）的DNA杂交， 在严格的杂交条件下。 这样的探针可用于例如与常染色体隐性性腰带肌营养不良症的诊断有关。 此外，通过使用直接DNA测序技术，鉴定这种突变能够诊断常染色体隐性的腰带肌营养不良症。
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公开(公告)号：US06262035B1
公开(公告)日：2001-07-17
申请号：US09164664
申请日：1998-10-01
申请人： Kevin P. Campbell , Kathleen H. Holt , Franck Duclos , Leland E. Lim , Volker Straub , Beverly Davidson , Roger Williamson
发明人： Kevin P. Campbell , Kathleen H. Holt , Franck Duclos , Leland E. Lim , Volker Straub , Beverly Davidson , Roger Williamson
IPC分类号： A01N4304
CPC分类号： C12N15/8509 , A01K67/0276 , A01K2207/15 , A01K2217/00 , A01K2217/075 , A01K2227/105 , A01K2267/0306 , A61K38/1709 , A61K48/00
摘要： Disclosed is a method for treating a patient suffering from the disease sarcoglycan-deficient limb-girdle muscular dystrophy by gene replacement therapy. Sarcoglycan gene replacement therapy produces extensive long-term expression of the sarcoglycan species which restores the entire sarcoglycan complex, results in the stable association of alph&agr;-dystroglycan with the sarcolemma, and eliminates the morphological markers of limb-girdle muscular dystrophy. In another aspect, the invention relates to a method for determining a specific defective sarcoglycan species in the tissue of a patient. The method involves culture of muscle cells obtained from the patient, and the independent introduction of expression vectors encoding each of the sarcoglycan species, &agr;, &bgr;, &ggr;, and &dgr;, into the cultured cells with subsequent assaying for restoration of the dystrophin-glycoprotein complex. In another aspect, the invention relates to a mouse, and cells derived therefrom, homozygous for a disrupted &agr;-sarcoglycan gene. The disruption prevents the synthesis of functional &agr;-sarcoglycan in cells of the mouse and results in the mutant mouse having no detectable sarcospan, &bgr;-, &ggr;-, &dgr;-sarcoglycan, and reduced &agr;-dystroglycan in the sarcolemma of skeletal and cardiac muscles, and a reduction of dystrophin in skeletal muscle, when compared to tissue of a mouse lacking a disrupted &agr;-sarcoglycan gene. In another aspect, the invention relates to methods for screening for therapeutic agents useful in the treatment of sarcoglycan-deficient limb-girdle muscular dystrophy. The methods involve administering a candidate therapeutic agent to a mouse, or cells derived therefrom, and assaying for therapeutic effects on the mouse or cells, with the determination of therapeutic effects being a reduction or reversal in disease progression, or a restoration of the dystroglycan complex.
摘要翻译： 本发明公开了一种通过基因替代疗法治疗患有疾病肌糖肌苷缺乏症的肢体肌营养不良症的患者的方法。 Sarcoglycan基因替代疗法产生广泛的长期表达的sarcoglycan物种，其恢复整个slegoglycan复合物，导致αphorpha-dystroglycan与肌膜的稳定关联，并消除肢体肌营养不良的形态学标志物。 另一方面，本发明涉及一种用于确定患者组织中的特定缺陷型糖团聚物物种的方法。 该方法包括从患者获得的肌肉细胞的培养，以及将编码每种肌糖原聚糖物质，α，β，γ和δ的表达载体独立引入培养的细胞中，随后测定肌营养不良蛋白 - 糖蛋白复合物的恢复 。 另一方面，本发明涉及一种小鼠及其衍生的细胞，用于破坏的α-丝裂霉素基因是纯合的。 该破坏阻止了小鼠细胞中功能性α-sarcoglycan的合成，并导致突变小鼠在骨骼肌和心脏肌肉的肌膜中不具有可检测的sarcospan，β - ，γ-，δ-色氨酸聚糖和还原的α-二糖聚糖， 和与缺乏α-sarcoglycan基因的小鼠的组织相比，骨骼肌中营养不良蛋白的减少。 另一方面，本发明涉及筛选用于治疗肌糖原缺乏型肢体肌营养不良症的治疗剂的方法。 所述方法包括将候选治疗剂施用于小鼠或由其衍生的细胞，以及测定对小鼠或细胞的治疗效果，其中治疗效果的确定是疾病进展中的减少或逆转，或者肌萎缩糖复合物的恢复 。
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公开(公告)号：US5837537A
公开(公告)日：1998-11-17
申请号：US719758
申请日：1996-09-25
申请人： Kevin P. Campbell , Daniel Jung , Franck Duclos , Volker Straub , John McPherson
发明人： Kevin P. Campbell , Daniel Jung , Franck Duclos , Volker Straub , John McPherson
CPC分类号： C07K14/4707
摘要： Disclosed herein is a substantially pure nucleic acid sequence encoding a mammalian 35 kDa non-dystrophin component (.delta.-sarcoglycan) of the dystrophin-glycoprotein complex. Also disclosed are the amino acid sequence and an immunogenic peptide of .delta.-sarcoglycan. The peptide when used to immunize a mammal, stimulates the production of antibodies which bind specifically to the .delta.-sarcoglycan. Methods to identify mutations in the .delta.-sarcoglycan gene associated with autosomal recessive limb-girdle muscular dystrophy are also disclosed. The identification of such mutations enables the design of nucleic acid probes which hybridize specifically to a mutant form of .delta.-sarcoglycan, or the complement thereof, but not to the DNA of the wild-type form of the gene (or the complement thereof), under stringent hybridization conditions. Such probes are useful, for example, in connection with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. In addition, the identification of such mutations enables the diagnosis of autosomal recessive limb-girdle muscular dystrophy through the use of direct DNA sequencing techniques.
摘要翻译： 本文公开了编码肌营养不良蛋白 - 糖蛋白复合物的哺乳动物35kDa非肌营养不良蛋白成分（δ-聚糖）的基本上纯的核酸序列。 还公开了δ-聚糖的氨基酸序列和免疫原性肽。 当肽用于免疫哺乳动物时，刺激产生与δ-聚糖结合特异性的抗体。 还公开了鉴定与常染色体隐性遗传性肢体肌营养不良症相关的δ-聚糖基因突变的方法。 这种突变的鉴定使得能够设计与δ-聚糖或其互补体的突变形式特异性杂交的核酸探针，而不与野生型形式的基因（或其补体）的DNA杂交， 在严格的杂交条件下。 这样的探针可用于例如与常染色体隐性性腰带肌营养不良症的诊断有关。 此外，通过使用直接DNA测序技术，鉴定这种突变能够诊断常染色体隐性的腰带肌营养不良症。
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公开(公告)号：US20110166081A1
公开(公告)日：2011-07-07
申请号：US12836874
申请日：2010-07-15
CPC分类号： A61K38/1703 , A61K9/0019 , A61K38/14
摘要： Disclosed is alpha-dystroglycan protein (alpha-DG) in glycosylated and functional form. The disclosed alpha-DG binds to the basal lamina and to the sarcolemma of muscle fibers and may be injected into muscle and incorporated into muscle fibers in order to restore membrane integrity where the muscle fibers comprise a dysfunctional alpha-DG protein. Alpha-DG as disclosed herein may be utilized in pharmaceutical compositions and methods for treating diseases and disorders associated with or characterized by a dysfunctional alpha-DG, such as muscular dystrophy.
摘要翻译： 公开了糖基化和功能形式的α-谷胱甘肽聚糖蛋白（α-DG）。 所公开的α-DG结合基底层和肌纤维的肌膜，并且可以注射到肌肉中并且并入肌肉纤维中，以便恢复膜完整性，其中肌纤维包含功能障碍的α-DG蛋白。 本文公开的α-DG可用于治疗与功能障碍性α-DG相关或特征在于肌营养不良症的疾病和病症的药物组合物和方法。
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9.发明授权Increasing functional glycosylation of alpha-dystroglycan in the treatment of muscle degeneration 有权增加α-dystrogly糖蛋白在肌肉退化治疗中的功能糖基化公开(公告)号：US08119766B2
公开(公告)日：2012-02-21
申请号：US11143885
申请日：2005-06-02
申请人： Kevin P. Campbell , Rita Barresi
发明人： Kevin P. Campbell , Rita Barresi
CPC分类号： C12N9/1048 , A61K38/1709 , A61K48/00 , C07K14/4707
摘要： Disclosed is a method for the prevention and/or treatment of muscle degeneration. In this method, a subject recognized as having muscle degeneration is treated with a composition effective to increase functional glycosylation of α-dystroglycan in an affected tissue in the subject. Functional glycosylation is to be increased to an extent wherein the binding of α-dystroglycan to its ligands in the affected tissue is rescued to levels substantially similar to those in an evenly matched tissue unaffected by degeneration. One effective means for increasing functional glycosylation of α-dystroglycan in a subject includes increasing glycosyltransferase activity, such as LARGE or LARGE2 activity, in the muscle of the subject. Therapeutic glycosylated peptide compositions are also provided.
摘要翻译： 公开了一种预防和/或治疗肌肉退化的方法。 在该方法中，被认为具有肌肉退化的受试者用有效增加受试者的受影响组织中α-肌浆聚糖功能性糖基化的组合物进行治疗。 功能性糖基化将被增加到其中α-dystroglylyc结合其受影响组织中的其配体的程度被挽救到基本上类似于不受退化影响的均匀匹配组织中的水平。 用于增加受试者中α-谷胱甘肽聚糖功能糖基化的一种有效方法包括在受试者的肌肉中增加糖基转移酶活性，如LARGE或LARGE2活性。 还提供了治疗性糖基化肽组合物。
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公开(公告)号：US06365337B1
公开(公告)日：2002-04-02
申请号：US09123030
申请日：1998-07-27
IPC分类号： G01N33567
CPC分类号： C07K14/705 , G01N33/6872
摘要： Disclosed are mammalian nucleic acid sequences encoding a neuronal-specific subunit of a voltage-gated calcium channel. Specifically disclosed are &ggr;2, &ggr;3 and &ggr;4 subunits. In other aspects, the disclosure relates to expression vectors which encode neuronal-specific subunits, as well as cells containing such vectors. In other aspects, the disclosure relates to antigenic fusion proteins comprising at least a portion of a mammalian neuronal-specific subunit of a voltage-gated calcium channel. Such fusion proteins are useful, for example, in the production of antibodies specifically reactive with the subunits of the invention. The nucleic acid sequences of the invention find application, for example, in screening for compounds which modulate the activity of neuronal voltage-gated calcium channels and also in diagnostic methods for diagnosing the autoimmune disease Lambert-Eaton Syndrome, as well as diagnosing defects in &ggr; subunit genes of a patient with a neuronal disease such as epilepsy. An additional application of the nucleic acid sequences of the invention is in therapeutic methods of treatment for such disorders.
摘要翻译： 公开了编码电压门控钙通道的神经元特异性亚基的哺乳动物核酸序列。 具体公开的是γ2，γ3和γ4亚基。 在其他方面，本公开涉及编码神经元特异性亚单位的表达载体以及含有该载体的细胞。 在其他方面，本公开涉及包含电压门控钙通道的哺乳动物神经元特异性亚基的至少一部分的抗原性融合蛋白。 这样的融合蛋白质可用于例如在与本发明的亚单位特异性反应的抗体的产生中。 本发明的核酸序列可用于例如筛选调节神经元电压门控钙通道活性的化合物，以及用于诊断自身免疫疾病兰伯特 - 伊顿综合征的诊断方法，以及诊断伽马 患有神经元疾病如癫痫患者的亚基基因。 本发明的核酸序列的另外的应用是治疗这些疾病的治疗方法。
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