公开(公告)号：US08409166B2

公开(公告)日：2013-04-02

申请号：US13094764

申请日：2011-04-26

申请人： Stephen M. Wiener ,  Robert F. Hoyt, Jr. ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brian Safer

发明人： Stephen M. Wiener ,  Robert F. Hoyt, Jr. ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brian Safer

IPC分类号： A61M31/00

CPC分类号： A61M25/1011 ,  A61B17/3417 ,  A61B2017/3425 ,  A61M25/02 ,  A61M25/04 ,  A61M2025/0233

摘要： Methods and devices are disclosed for selective delivery of therapeutic substances to specific histologic or microanatomic areas of organs. Introduction of the therapeutic substance into a hollow organ space (such as an hepatobiliary duct or the gallbladder lumen) at a controlled pressure, volume or rate allows the substance to reach a predetermined cellular layer (such as the ephithelium or sub-epithelial space). The volume or flow rate of the substance can be controlled so that the intralumenal pressure reaches a predetermined threshold level beyond which subsequent subepithelial delivery of the substance occurs. Alternatively, a lower pressure is selected that does not exceed the threshold level, so that delivery occurs substantially only to the epithelial layer. Such site specific delivery of therapeutic agents permits localized delivery of substances (for example to the interstitial tissue of an organ) in concentrations that may otherwise produce systemic toxicity. Occlusion of venous or lymphatic drainage from the organ can also help prevent systemic administration of therapeutic substances, and increase selective delivery to superficial epithelial cellular layers. Delivery of genetic vectors can also be better targeted to cells where gene expression is desired. The access device comprises a cannula with a wall piercing tracar within the lumen. Two axially spaced inflatable balloons engage the wall securing the cannula and sealing the puncture site. A catheter equipped with an occlusion balloon is guided through the cannula to the location where the therapeutic substance is to be delivered.

摘要翻译： 公开了用于将治疗物质选择性递送到器官的特定组织学或微解剖区域的方法和装置。 以受控的压力，体积或速率将治疗物质引入中空器官空间（例如肝胆管或胆囊腔）中允许物质到达预定的细胞层（例如上睑或上皮上皮空间）。 可以控制物质的体积或流速，使得腔内压力达到预定阈值水平，超过此阈值水平发生物质的后续上皮下递送。 或者，选择不超过阈值水平的较低压力，使得递送基本上仅发生在上皮层。 治疗剂的这种位点特异性递送允许以另外可能产生全身毒性的浓度局部递送物质（例如，器官的间质组织）。 从器官中静脉或淋巴引流的阻塞还可以帮助防止治疗物质的全身给药，并增加对表面上皮细胞层的选择性递送。 遗传载体的递送也可以更好地靶向需要基因表达的细胞。 进入装置包括在管腔内具有穿孔孔的套管。 两个轴向间隔开的可充气气囊与固定插管并密封穿刺部位的壁接合。 配备有闭塞气囊的导管通过套管被引导到治疗物质要被输送的位置。

公开(公告)号：US20080269718A1

公开(公告)日：2008-10-30

申请号：US12009646

申请日：2008-01-17

申请人： Stephen M. Wiener ,  Robert F. Hoyt ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brian Safer

发明人： Stephen M. Wiener ,  Robert F. Hoyt ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brian Safer

IPC分类号： A61M5/00

CPC分类号： A61M25/1011 ,  A61B17/3417 ,  A61B2017/3425 ,  A61M25/02 ,  A61M25/04 ,  A61M2025/0233

摘要： Methods and devices are disclosed for selective delivery of therapeutic substances to specific histologic or microanatomic areas of organs. Introduction of the therapeutic substance into a hollow organ space (such as an hepatobiliary duct or the gallbladder lumen) at a controlled pressure, volume or rate allows the substance to reach a predetermined cellular layer (such as the ephithelium or sub-epithelial space). The volume or flow rate of the substance can be controlled so that the intralumenal pressure reaches a predetermined threshold level beyond which subsequent subepithelial delivery of the substance occurs. Alternatively, a lower pressure is selected that does not exceed the threshold level, so that delivery occurs substantially only to the epithelial layer. Such site specific delivery of therapeutic agents permits localized delivery of substances (for example to the interstitial tissue of an organ) in concentrations that may otherwise produce systemic toxicity. Occlusion of venous or lymphatic drainage from the organ can also help prevent systemic administration of therapeutic substances, and increase selective delivery to superficial epithelial cellular layers. Delivery of genetic vectors can also be better targeted to cells where gene expression is desired. The access device comprises a cannula with a wall piercing tracar within the lumen. Two axially spaced inflatable balloons engage the wall securing the cannula and sealing the puncture site. A catheter equipped with an occlusion balloon is guided through the cannula to the location where the therapeutic substance is to be delivered.

摘要翻译： 公开了用于将治疗物质选择性递送到器官的特定组织学或微解剖区域的方法和装置。 以受控的压力，体积或速率将治疗物质引入中空器官空间（例如肝胆管或胆囊腔）中允许物质到达预定的细胞层（例如上睑或上皮上皮空间）。 可以控制物质的体积或流速，使得腔内压力达到预定阈值水平，超过此阈值水平发生物质的后续上皮下递送。 或者，选择不超过阈值水平的较低压力，使得递送基本上仅发生在上皮层。 治疗剂的这种位点特异性递送允许以另外可能产生全身毒性的浓度局部递送物质（例如，器官的间质组织）。 从器官中静脉或淋巴引流的阻塞还可以帮助防止治疗物质的全身给药，并增加对表面上皮细胞层的选择性递送。 遗传载体的递送也可以更好地靶向需要基因表达的细胞。 进入装置包括在管腔内具有穿孔孔的套管。 两个轴向间隔开的可充气气囊与固定插管并密封穿刺部位的壁接合。 配备有闭塞气囊的导管通过套管被引导到治疗物质要被输送的位置。

公开(公告)号：US20110263974A1

公开(公告)日：2011-10-27

申请号：US13094764

申请日：2011-04-26

申请人： Stephen M. Wiener ,  Robert F. Hoyt, JR. ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brain Safer

发明人： Stephen M. Wiener ,  Robert F. Hoyt, JR. ,  John R. Deleonardis ,  Randall R. Clevenger ,  Robert J. Lutz ,  Douglas V. Christini ,  Brain Safer

IPC分类号： A61M5/14 ,  A61B6/00 ,  A61M5/00

CPC分类号： A61M25/1011 ,  A61B17/3417 ,  A61B2017/3425 ,  A61M25/02 ,  A61M25/04 ,  A61M2025/0233

摘要： Methods and devices are disclosed for selective delivery of therapeutic substances to specific histologic or microanatomic areas of organs. Introduction of the therapeutic substance into a hollow organ space (such as an hepatobiliary duct or the gallbladder lumen) at a controlled pressure, volume or rate allows the substance to reach a predetermined cellular layer (such as the ephithelium or sub-epithelial space). The volume or flow rate of the substance can be controlled so that the intralumenal pressure reaches a predetermined threshold level beyond which subsequent subepithelial delivery of the substance occurs. Alternatively, a lower pressure is selected that does not exceed the threshold level, so that delivery occurs substantially only to the epithelial layer. Such site specific delivery of therapeutic agents permits localized delivery of substances (for example to the interstitial tissue of an organ) in concentrations that may otherwise produce systemic toxicity. Occlusion of venous or lymphatic drainage from the organ can also help prevent systemic administration of therapeutic substances, and increase selective delivery to superficial epithelial cellular layers. Delivery of genetic vectors can also be better targeted to cells where gene expression is desired. The access device comprises a cannula with a wall piercing tracar within the lumen. Two axially spaced inflatable balloons engage the wall securing the cannula and sealing the puncture site. A catheter equipped with an occlusion balloon is guided through the cannula to the location where the therapeutic substance is to be delivered.

摘要翻译： 公开了用于将治疗物质选择性递送到器官的特定组织学或微解剖区域的方法和装置。 以受控的压力，体积或速率将治疗物质引入中空器官空间（例如肝胆管或胆囊腔）中允许物质到达预定的细胞层（例如上睑或上皮上皮空间）。 可以控制物质的体积或流速，使得腔内压力达到预定阈值水平，超过此阈值水平发生物质的后续上皮下递送。 或者，选择不超过阈值水平的较低压力，使得递送基本上仅发生在上皮层。 治疗剂的这种位点特异性递送允许以另外可能产生全身毒性的浓度局部递送物质（例如，器官的间质组织）。 从器官中静脉或淋巴引流的阻塞还可以帮助防止治疗物质的全身给药，并增加对表面上皮细胞层的选择性递送。 遗传载体的递送也可以更好地靶向需要基因表达的细胞。 进入装置包括在管腔内具有穿孔孔的套管。 两个轴向间隔开的可充气气囊与固定插管并密封穿刺部位的壁接合。 配备有闭塞气囊的导管通过套管被引导到治疗物质要被输送的位置。

公开(公告)号：US06821511B2

公开(公告)日：2004-11-23

申请号：US09922327

申请日：2001-08-03

申请人： Robert M. Kotin ,  Brian Safer ,  John A. Chiorini ,  Matthew D. Weitzman ,  Roland A. Owens ,  Stephen M. Wiener

发明人： Robert M. Kotin ,  Brian Safer ,  John A. Chiorini ,  Matthew D. Weitzman ,  Roland A. Owens ,  Stephen M. Wiener

IPC分类号： A61K4800

CPC分类号： C12N15/86 ,  A61K38/37 ,  A61K38/4846 ,  A61K48/00 ,  C07K14/005 ,  C07K14/245 ,  C07K14/745 ,  C07K14/755 ,  C07K2319/00 ,  C12N7/00 ,  C12N15/90 ,  C12N2750/14122 ,  C12N2750/14143 ,  C12N2750/14162

摘要： A composition for delivering at least one DNA sequence encoding a desired protein or polypeptide (such as a therapeutic agent) to a cell. The composition comprises an adeno-associated virus rep protein (or a nucleic acid sequence encoding an adeno-associated virus rep protein) and a genetic construct including at least one DNA sequence encoding a protein or polypeptide or genetic transcript of interest and a promoter controlling the at least one DNA sequence. The genetic construct also includes a first adeno-associated virus ITR or protein or derivative thereof and a second adeno-associated virus ITR or a portion or derivative thereof. The first and second adeno-associated virus ITRs or portions or derivatives thereof flank the at least one DNA sequence encoding the protein or polypeptide or genetic transcript of interest and the promoter controlling the at least one DNA sequence encoding the protein or polypeptide or genetic transcript of interest. Such a composition provides for integration of genetic material at a specific locus in the human chromosome, while minimizing the possibility of inadvertent inactivation of host genes and minimizing the possibility of viral contamination.

摘要翻译： 用于将至少一种编码所需蛋白质或多肽（例如治疗剂）的DNA序列递送至细胞的组合物。 组合物包含腺相关病毒rep蛋白（或编码腺相关病毒rep蛋白的核酸序列）和遗传构建体，其包含至少一个编码目的蛋白质或多肽的遗传转录物的DNA序列，以及控制 至少一个DNA序列。 遗传构建体还包括第一腺相关病毒ITR或其蛋白质或其衍生物和第二腺相关病毒ITR或其部分或衍生物。 第一和第二腺相关病毒ITR或其部分或衍生物位于编码目标蛋白质或多肽或遗传转录物的至少一个DNA序列和控制编码蛋白质或多肽的至少一个DNA序列或遗传转录物 利益。 这样的组合物提供了遗传物质在人染色体的特定位点的整合，同时最小化宿主基因无意灭活的可能性并使病毒污染的可能性最小化。

公开(公告)号：US06342390B1

公开(公告)日：2002-01-29

申请号：US08344729

申请日：1994-11-23

申请人： Stephen M. Wiener ,  John A. Chiorini ,  Brian Safer ,  Robert M. Kotin ,  Matthew D. Weitzman ,  Roland A. Owens

发明人： Stephen M. Wiener ,  John A. Chiorini ,  Brian Safer ,  Robert M. Kotin ,  Matthew D. Weitzman ,  Roland A. Owens

IPC分类号： C12N1500

CPC分类号： C12N15/86 ,  A61K38/37 ,  A61K38/4846 ,  A61K48/00 ,  C07K14/005 ,  C07K14/245 ,  C07K14/745 ,  C07K14/755 ,  C07K2319/00 ,  C12N7/00 ,  C12N15/90 ,  C12N2750/14122 ,  C12N2750/14143 ,  C12N2750/14162

摘要： A composition for delivering at least one DNA sequence encoding a desired protein or polypeptide (such as a therapeutic agent) to a cell. The composition comprises an adeno-associated virus rep protein (or a nucleic acid sequence encoding an adeno-associated virus rep protein) and a genetic construct including at least one DNA sequence encoding a protein or polypeptide or genetic transcript of interest and a promoter controlling the at least one DNA sequence. The genetic construct also includes a first adeno-associated virus ITR or protein or derivative thereof and a second adeno-associated virus ITR or a portion or derivative thereof. The first and second adeno-associated virus ITRs or portions or derivatives thereof flank the at least one DNA sequence encoding the protein or polypeptide or genetic transcript of interest and the promoter controlling the at least one DNA sequence encoding the protein or polypeptide or genetic transcript of interest. Such a composition provides for integration of genetic material at a specific locus in the human chromosome, while minimizing the possibility of inadvertent inactivation of host genes and minimizing the possibility of viral contamination.

摘要翻译： 用于将至少一种编码所需蛋白质或多肽（例如治疗剂）的DNA序列递送至细胞的组合物。 组合物包含腺相关病毒rep蛋白（或编码腺相关病毒rep蛋白的核酸序列）和遗传构建体，其包含至少一个编码目的蛋白质或多肽的遗传转录物的DNA序列，以及控制 至少一个DNA序列。 遗传构建体还包括第一腺相关病毒ITR或其蛋白质或其衍生物和第二腺相关病毒ITR或其部分或衍生物。 第一和第二腺相关病毒ITR或其部分或衍生物位于编码目标蛋白质或多肽或遗传转录物的至少一个DNA序列和控制编码蛋白质或多肽的至少一个DNA序列或遗传转录物 利益。 这样的组合物提供了遗传物质在人染色体的特定位点的整合，同时最小化宿主基因无意灭活的可能性并使病毒污染的可能性最小化。