EP1532255A1 - Methodes d'administration d'agents de therapie genique - Google Patents

Methodes d'administration d'agents de therapie genique

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Publication number
EP1532255A1
EP1532255A1 EP03761219A EP03761219A EP1532255A1 EP 1532255 A1 EP1532255 A1 EP 1532255A1 EP 03761219 A EP03761219 A EP 03761219A EP 03761219 A EP03761219 A EP 03761219A EP 1532255 A1 EP1532255 A1 EP 1532255A1
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EP
European Patent Office
Prior art keywords
gene therapy
catheter
pressure
vasculature
organ
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03761219A
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German (de)
English (en)
Inventor
Kevin M. Baskin
Simon J. Eastman
Ronald K. Scheule
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Genzyme Corp
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Genzyme Corp
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Publication date
Application filed by Genzyme Corp filed Critical Genzyme Corp
Publication of EP1532255A1 publication Critical patent/EP1532255A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0083—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the administration regime

Definitions

  • the present invention relates to methods for the administration of therapeutic agents to a target organ of a mammalian subject. More specifically, the invention relates to gene delivery methods whereby a target organ, such as the liver, is isolated and treated employing a minimally invasive, percutaneous transcatheter procedure. The present invention further relates to pressure-enhanced delivery of gene therapy agents directly to the isolated vasculature of a target organ. Methods for targeted gene delivery to the mammalian liver as a whole, or a single hepatic lobe, are disclosed.
  • Gene therapy is the intracellular delivery of exogenous genetic material that corrects an existing defect or provides a new beneficial function to the cells.
  • the liver is an important target organ for gene therapy because of its central role in metabolism and production of serum proteins.
  • Familial hypercholesterolemia, hemophilia, lysosomal storage diseases (including Gaucher's and Fabry diseases) are just a few examples.
  • Many such diseases may be amenable to gene therapy (Siatskas et al., J. Inherit Metab. Dis. 2001 , 24(Suppl. 2): 25-41 ; Barranger et al., Expert Opin. Biol. Ther. 2001 , 1(5): 857-867; Barranger et al., Neurochem. Res. 1999, 24(5): 601-615).
  • adenoviral gene transfer vectors When adenoviral gene transfer vectors are injected into the portal vein of a rat, high levels of transgene expression are observed in the liver (Rosefeld et al., Science 1991 , 252: 431-434), but such expression is transient and requires repeated injections of the vector. Additionally, when injected in the circulatory system, pre-existing antibodies may quickly neutralize viral vectors. Systemic injections of recombinant adenoviral vectors have shown that a neutralizing host immune response limits the effectiveness of such vectors in repeated injections (Yang et al., Proc. Natl.
  • AAV adenoassociated virus
  • Non-viral gene transfer methods such as injection of "naked” plasmid DNA, have also been described.
  • the levels of gene transfer are generally too low to be sufficient for clinical applications (Malone et al., J. Biol. Chem. 1994, 269: 29903-29907; Hickman et al. Hum. Gene Ther.1994, 5:1477-1483).
  • Cationic liposome-mediated gene transfer was found to be much more efficient than transfection with naked plasmid DNA, but the level of gene transfer usually is still not as high as with viral vectors (Liu et al., J. Biol. Chem. 1995, 270: 24864-24870).
  • Figure 1 illustrates a lobar delivery method of hepatic gene therapy utilizing a balloon occlusion balloon catheter introduced through a jugular vein; other transvascular routes, such as a femoral vein, could also be used.
  • Figure 2 shows the distribution of gene expression in hepatic parenchymal tissue approximately 24 hours following lobar delivery.
  • Figure 3 illustrates the distribution of the gene therapy agent following a high-pressure lobar injection into a single hepatic lobe using the hepatic vein combined with inferior vena cava outflow blockage.
  • Figure 4 illustrates targeted whole-organ delivery using a three- catheter approach.
  • Figure 5 shows the distribution of gene expression following targeted whole-organ delivery through the vena cava combined with outflow blockage.
  • Figure 6 illustrates a double catheter method for whole-organ delivery to the liver through controlled-pressure injection into the vena cava combined with outflow blockage of the liver.
  • Figure 7 depicts a catheter system for controlled-pressure targeted whole-organ delivery to the liver through injection into the vena cava combined with outflow blockage of the liver.
  • Figure 8 illustrates the placement of a single catheter for targeted whole-organ delivery to the liver through injection into the vena cava combined with outflow blockage of the liver.
  • Figure 9 shows representative pressure profiles in the isolated hepatic vasculature between the two occlusion balloons during injection of various volumes (5, 10, and 15 ml/kg of body weight) of DNA-containing solution.
  • the basal vena cava pressures have been subtracted so that the data represent the change in pressure during injection. Pressure was monitored by coupling the injection lumen(s) of one or both of the balloon catheters to the transducer(s) of a blood pressure analyzer.
  • Figure 10 shows SEAP expression in the serum of rabbits 24 hours post-transfection of various volumes (5, 10, and 15 ml/kg body weight) of DNA- containing solution.
  • the present invention relates to methods by which a depot organ, such as the mammalian liver, is isolated and treated with a therapeutic agent, such as in gene therapy.
  • the methods of the invention employ a minimally invasive, catheter-based procedure.
  • a balloon- occlusion balloon catheter is engaged proximally in a single hepatic vein and a therapeutic solution is hydrodynamically delivered beyond the inflated (occluding) balloon via a catheter to the liver parenchyma through the vessels of the thus-isolated target lobe (referred to herein as "lobar delivery").
  • lobar delivery The rapid rate of injection produces a desired transient increase in pressure within the isolated section of the vasculature.
  • an endovascular injection catheter with side holes positioned beyond the balloon in a hepatic vein can be used to treat a given hepatic lobe.
  • venous outflow from the entire organ is temporarily occluded by the placement of balloon catheters in the inferior vena cava both proximal and distal to the hepatic venous outflow, and the gene therapy agent is injected via an endovascular injection catheter in the space between the inflated (occluding) balloons at a rate and volume sufficient to elevate pressure at least transiently and to fill the isolated vascular tree supplying or draining the subtending organ parenchyma (referred to herein as targeted whole-organ delivery).
  • targeted whole-organ delivery referred to herein as targeted whole-organ delivery
  • the gene therapy solution is hydrodynamically injected at a rate sufficient to result in a pressure increase chosen from the ranges of 10 to 100, 10 to 80, 10 to 50, 20 to 100, 20 to 80, and 20 to 50 mmHg.
  • the pressure increase is chosen from the ranges of 15 to 100, 15 to 80, 15 to 50, 10 to 30, and 10 to 20 mmHg.
  • the pressure increase is at least 15 mmHg.
  • the catheters are rated to withstand injection pressures of at least 300 psi, and preferably 1200 psi.
  • polynucleotide refers to deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA).
  • RNA ribonucleic acid
  • the term should also be understood to include, as equivalents, nucleotide analogs, and single or double stranded polynucleotides. Examples of polynucleotides include, but are not limited to, plasmid DNA or fragments thereof, viral DNA or RNA, anti- sense RNA, etc.
  • plasmid DNA refers to double stranded DNA that is circular.
  • transgene refers to a polynucleotide that is introduced into the cells of a tissue or an organ and is capable of being expressed under appropriate conditions, or otherwise conferring a beneficial property to the cells.
  • a transgene is selected based upon a desired therapeutic outcome. It may encode, for example, hormones, enzymes, receptors, or other proteins of interest. For instance, in the treatment of familial hypercholesterolemia, one may use a transgene encoding LDL receptor (Kobayashi et al., J. Biol. Chem. 271 : 6852-6860).
  • transfection is used interchangeably with the term “gene transfer” and means the intracellular introduction of a polynucleotide.
  • Transfection efficiency refers to the relative amount of the transgene taken up by the cells subjected to transfection. In practice, transfection efficiency is estimated by the amount of the reporter gene product expressed following the transfection procedure.
  • transfection agent used interchangeably with the terms “gene therapy agent” and “therapeutic agent,” refers to any solution, mixture, or other formulation containing a polynucleotide to be delivered intracellularly.
  • a transfection agent usually includes a carrier polynucleotide, termed “expression vector,” also known as “gene delivery vector,” linked to a transgene and, optionally, other compounds that may facilitate the transfer of the polynucleotide across the cell wall. Typically, such compounds reduce the electrostatic charge of the cell surface and the polynucleotide itself, or increase the permeability of the cell wall.
  • Examples include cationic liposomes, calcium phosphate, polylysine, vascular endothelial growth factor (VEGF), etc.
  • Hypertonic solutions containing, for example, NaCI, sugars, or polyols, can also be used to increase the extracellular osmotic pressure thereby increasing transfection efficiency.
  • the gene therapy solutions may also include enzymes such as proteases and lipases, mild detergents and other compounds that increase permeability of cell membranes.
  • the methods of the invention are not limited to any particular composition of the transfection agent and can be practiced with any suitable agent so long as it is not toxic to the subject or its toxicity is within acceptable limits.
  • hydrodynamic injection refers to an intravascular injection at a rate and volume sufficient to generate supra-systemic pressure within the vascular space and the subtending organ parenchyma. This pressure increase may be transient, as in a systemic injection without outflow blockade, or prolonged, as in a targeted whole-organ injection with outflow blockade. Hydrodynamic injection may be rate- and volume-controlled by a power injector device programmed to deliver a given volume of therapeutic agent in solution at a given rate. A hydrodynamic injection may also be pressure-controlled, by regulating the power injector by a feedback mechanism that monitors the intravascular or intraparenchymal pressure during the injection cycle.
  • controlled-pressure injections Both rate-controlled and pressure-controlled hydrodynamic injections are referred to herein as "controlled-pressure injections".
  • the methods of invention can be practiced with any suitable pressure profile, without regard to rate of rise, peak pressure, or duration so long as the method is not unduly injurious to the subject.
  • a salient feature in the methods of the present invention is that delivery of a gene therapy agent to isolated segments of an organ's vasculature is performed under increased pressure in that segment or segments.
  • the temporary pressure increase is achieved by a hydrodynamic injection of the therapeutic solution. This increase in pressure corresponds to the difference in pressure in the isolated segment of the body vasculature immediately prior to injection and the elevated or supra-systemic pressure during injection.
  • the total volume of injection (usually about 10-50% of the volume of a target organ) is hydrodynamically injected at a rate sufficient to result in a pressure increase chosen from the ranges of 10 to 100, 10 to 80 mmHg, 10 to 50, 20 to 100, 20 to 80, and 20 to 50 mmHg.
  • the pressure increase is chosen from the ranges of 15 to 100, 15 to 80, 15 to 50, 10 to 30, and 10 to 20 mmHg.
  • the pressure increase is at least 15 mmHg.
  • the catheters are rated to withstand injection pressures of at least 300 psi, and preferably 1200 psi.
  • a single lobe of the liver is transfected using a controlled-pressure injection.
  • a catheter is advanced, using known interventional and surgical techniques, through the vena cava and into the desired hepatic vein, as depicted in Figure 1.
  • a balloon occlusion balloon catheter is placed within the lumen of a selected hepatic vein following introduction of the catheter through either the jugular or femoral veins.
  • a balloon on the catheter is inflated to block venous outflow, thus confining the injected solution to the parenchyma of the isolated target lobe.
  • a single hepatic lobe is transfected under controlled-pressure conditions.
  • a balloon occlusion balloon catheter (as depicted in Figure 3), or an endovascular injection catheter with distal sideholes, is placed within the lumen of a selected hepatic vein.
  • An occluding balloon is placed in the hepatic portion of the inferior vena cava to block hepatic venous outflow.
  • the balloon Before transcatheter injection of the transfection agent, the balloon is inflated to block venous outflow, thus confining the injected solution to the parenchyma of the isolated target lobe. Injecting through a catheter with side holes allows a higher rate of injection because it reduces the risk of ballistic injury to the tissues due to greater dispersion of the injected solution.
  • a single lobe is transfected using a hydrodynamic injection.
  • a balloon occlusion balloon catheter is placed within the lumen of a selected hepatic vein.
  • An endovascular injection catheter with side- holes near the tip is advanced through the vena cava into the selected hepatic vein and positioned with the side holes beyond the balloon occlusion balloon.
  • the balloon occlusion balloon is inflated to block venous outflow, thus confining the injected solution to the parenchyma of the isolated target lobe.
  • the transfection agent is delivered to the entire liver with a single hydrodynamic injection.
  • the liver is isolated through the use of balloons delivered via two separate dual-lumen catheters, inflated in the inferior vena cava both superior and inferior to the hepatic venous outflow.
  • the transfection agent is then injected through an endovascular catheter with side holes positioned between the balloons and flows in a retrograde fashion through the hepatic veins to the entire hepatic parenchyma.
  • the endovascular catheter with side holes may be incorporated with one of the balloon occlusion balloon catheters, reducing the number of catheters that must be deployed, and eliminating loss of pressure alongside the delivery catheter.
  • Catheters can be delivered transvascularly using a minimally invasive image- guided percutaneous technique rather than open surgical cutdown to the vessel achieve blockade of target organ vascular outflow.
  • the balloons are sized to each patient's vessels to assure atraumatic blockage of target-organ vascular outflow during the procedure.
  • the desired solution is injected at controlled rate and volume into the isolated vascular space through the catheter.
  • a constricting band may be applied across the subject's abdomen over the liver to limit the volume of injected solution required to generate a given pressure by limiting expansion of the isolated organ during the injection.
  • Physical methods such as, for example, electroporation and ultrasound- mediated sonoporation with or without microbubbles (microbubble booster), may be used with the methods of this invention to increase transfection efficiency.
  • the ultrasound treatment concurrent with transfection may be used in conjunction with catheter-based localized delivery to effectuate the same therapeutic result using lower volumes of injection.
  • Standard therapeutic ultrasound conditions (1 MHz) can be used to enhance the permeabilization of the liver.
  • Ultrasound may be applied transcutaneously over the liver prior to, concurrently with, or following delivery of the transfection agent.
  • the solution of gene therapy agent may be prepared to contain gaseous microbubbles
  • microbubble booster (0.1 to 100 ⁇ m in diameter) also known as microbubble booster.
  • the methods of the present invention involve the use of a transfection agent in the course of gene therapy, however, the methods apply equally well to therapeutic injections of chemotherapeutic or other pharmaceutical agents, stem cells, or imaging contrast materials where targeted delivery of a diagnostic or therapeutic solution at controlled pressure to an isolated organ is desired.
  • the following representative examples are intended to illustrate, but not limit, the present invention. While the representative procedures are performed in rabbits, they are successfully performed within parameters clinically feasible in human subjects.
  • New Zealand White rabbits were obtained from Millbrook Breeding Lab (Amherst, MA). Catheters and guidewires were obtained from Boston Scientific (Natick, MA) or Cook (Bloomington, IN). The power injector and Optiray 350 contrast medium were obtained from Mallinckrodt (Hazelwood, MO). Pressure in the isolated section of the vasculature was measured through one of the (non-injecting) balloon catheters using a Blood Pressure Analyzer (Micro-Med, Louisville, KY). Under the conditions described in the examples, an increase of 10- 60 mmHg in pressure was achieved for injection rates of 5 to 15 ml/sec.
  • the jugular vein of a rabbit was accessed through a 2.5 cm paramedian longitudinal incision beginning at the inferior margin of the mandible and extending caudally.
  • a balloon occlusion balloon catheter was advanced through the vena cava and into the desired hepatic vein as depicted in Figure 1.
  • the muscle fascia was bluntly dissected to expose the right external jugular vein.
  • a 20-gauge angiocatheter needle was inserted into the jugular vein.
  • an image- guided percutaneous needle an approach more likely to be employed in humans, can be used to access the vein.
  • a 0.018-inch Teflon- coated guidewire was placed coaxially through the angiocatheter and guided into a hepatic vein under fluoroscopic guidance.
  • the angiocatheter was exchanged over the guidewire for a 5 French balloon occlusion balloon catheter that was guided selectively into the target hepatic lobar vein.
  • the guide wire was removed and a small amount of non-ionic iodinated contrast agent was injected to confirm proper positioning fluoroscopically.
  • the balloon occlusion balloon was inflated with contrast and occlusion of the selected vessel confirmed by injection of a small volume of contrast.
  • pGZB- ⁇ galactosidase A ( ⁇ -gal) plasmid in saline (with or without 7.5-15% mannitol) was then injected through the endovascular catheter into the isolated lobe at varying rates.
  • the features of the pCF1-SEAP plasmid are described in Yew, et. al., Hum. Gen Ther. 1997, 8: 575-584.
  • the pCF1-SEAP plasmid contains a reporter gene of a secreted form of alkaline phosphatase (SEAP).
  • SEAP alkaline phosphatase
  • the pGZB-sCAT plasmid contains a reporter gene for intracellular (tissue) expression of the reporter gene product chloramphenicol acetyltransferase (CAT).
  • Alpha-galactosidase is an enzyme that catase is an enzyme that produces a reporter gene of a secreted form of alkaline phosphatase (SEAP).
  • SEAP alkaline phosphatase
  • CAT chloramphenicol acetyltransferase
  • rabbit serum was heated to 65°C to denature endogenous alkaline phosphatase
  • Serum SEAP levels were in the range of 1-50 ⁇ g/ml, as shown in Table 1. These levels are 16 to 800 times lower than the levels achieved in a mouse following high-volume (hydrodynamic) tail vein injection. The efficiency of transfection was dependent on the volume of injection, the rate of injection and the DNA concentration employed.
  • the assay was performed according to the procedure described in Ziegler et al., Hum. Gene Ther. 1999, 10:1667-1682.
  • the levels of alpha-galactosidase expression shown in Figure 2, confirm that redistribution of the injection to the non-isolated portions of the liver occurs. Portal redistribution results in levels of transfection that are an order of magnitude lower than the corresponding levels in the isolated target lobe. However, due to portal redistribution, the level of alpha-galactosidase expression even in the non- isolated liver is still significantly above the level that can be achieved with low- pressure (non-hydrodynamic) systemic injections. Table 1 Levels of SEAP expression following transfection using lobar delivery
  • the lobar delivery method as described in Example 1, restricts high- pressure delivery to a portion of the depot organ distal to the occlusion balloon.
  • outflow blockade of all hepatic veins can be achieved by covering the hepatic venous ostia with a balloon catheter deployed in the hepatic vena cava.
  • the femoral vein was accessed from the medial thigh via a longitudinal skin incision extending inferiorly from the femoral groove. Muscle fascia was bluntly dissected to expose the neurovascular bundle. The femoral vein was carefully dissected from the associated artery and nerve. A 1-2 cm segment of the femoral vein was isolated and ligated distally. A 7 French introducer sheath was inserted into the femoral vein, proximal to the ligation. A guidewire was advanced into the inferior vena cava using fluoroscopic guidance.
  • a 5 French catheter with a 14 mm by 4 cm noncompliant balloon was passed through the sheath over the guidewire into the hepatic portion of the vena cava.
  • the outer diameter of the sheath is large relative to the rabbit femoral vein, making this procedure difficult to replicate in the rabbit model without vascular injury. This complication is not expected in human subjects.
  • the rabbit was systemically heparinized.
  • the balloon was inflated just prior to injection of the transfection agent via the balloon occlusion balloon catheter placed in a hepatic vein.
  • a small amount of radiographic contrast was injected through the introducer sheath to ensure that the balloon obstructed flow in the inferior vena cava.
  • 70 ml of transfection agent containing 7 mg of the pCF1-SEAP plasmid and 15% mannitol in saline was then injected through the endovascular catheter into a single isolated lobe at the rate of 5 ml/sec.
  • the catheters and sheath were withdrawn and hemostasis was achieved.
  • Dense radiographic contrast as seen in Figure 3, enhanced the isolated lobe, while more dilute contrast recirculated in a retrograde fashion to the remainder of the liver via the portal vein.
  • the level of serum SEAP was 37 ⁇ g/ml as measured by the procedure
  • the concentrations of serum SEAP achieved in the serum of rabbits treated with this method ranged from 0.2 to 0.8 ⁇ g/ml as measured by the procedure described in Example 1. Because a much greater proportion of the portal vein is extrahepatic in rabbits than in humans, access using this approach and adequate hemostasis following the procedure are difficult to achieve. For this reason, outflow blockade was not attempted and suprasystemic pressures were not achieved during injection. These factors are not expected to be limiting for the equivalent procedure in human subjects.
  • Example 4 Targeted Whole-Organ Delivery To deliver a gene therapy agent to the entire liver with a single hydrodynamic injection, the liver is isolated through the use of balloons inflated in the inferior vena cava both superior and inferior to the hepatic venous outflow. The transfection agent solution is then injected between the balloons and flows in a retrograde fashion through the hepatic veins to the entire hepatic parenchyma.
  • This method is shown in Figure 4.
  • balloon occlusion balloons are advanced from above through the jugular vein to a position in the inferior vena cava between the right atrium and the most superior hepatic vein, and from below through a femoral vein to a position in the inferior vena cava between the most superior renal vein and the most inferior hepatic vein.
  • a 4 French pigtail catheter with multiple side holes near the tip is advanced through the opposite femoral vein to a position in the inferior vena cava between the two balloon occlusion balloons.
  • the balloons are inflated to isolate the liver immediately prior to the injection of the gene therapy solution via the pigtail catheter.
  • the balloon occlusion balloons may be delivered via two separate dual-lumen catheters, as depicted in Figure 6, or via a single four-lumen catheter, as shown in Figure 7 and Figure 8.
  • Injections at sufficient rate and volume to achieve high levels of gene transfection may cause transient cardiodynamic instability (bradycardia and hypotension) that appear to be related to a vasovagal response to stretching of the vessels and the hepatic capsule during injection, as well as to the rapid volume loading that accompanies the injection.
  • Pre-treatment of the rabbits with an anticholinergic agent such as glycopyrrolate just prior to injection prevents this response.
  • the transfection agent solution contained 100 ⁇ g/ml of the pGZB-sCAT plasmid , 100 ⁇ g/ml of the pCF1-SEAP plasmid and 15% mannitol in saline solution and was injected at rate of 8-10 ml/sec. Eliminating mannitol from this solution resulted in increased expression and lower toxicity.
  • the observed levels of serum SEAP were within between 1/20th and 1/2 those in a mouse following hydrodynamic tail vein injections, as measured by the procedure described in Example 1. The results of the SEAP measurements are represented in Table 2.
  • FIG. 10 shows SEAP expression in the serum of rabbits 24 hours post- transfection of various volumes (5, 10, and 15 ml/kg body weight) of DNA- containing solution. All animals were injected at the rate of 10 ml/sec with the same dose of DNA (2.5 mg/kg pCF1-SEAP with or without 2.0 mg/kg pGZB-sCAT). Addition of pGZB-sCAT had no effect on SEAP expression levels.

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Abstract

L'invention concerne des procédés d'administration à pression supérieure de divers agents thérapeutiques, tels que des agents de thérapie génique, dans un système vasculaire d'un organe cible chez un mammifère. L'invention concerne des méthodes de thérapie génique ciblée appliquées dans le foie d'un mammifères, ou dans un seul lobe hépatique. Ces méthodes sont fondées sur des procédures utilisant un cathéter à invasion minimale qui permettent d'isoler un organe cible et de le traiter localement au moyen d'un agent de thérapie génique. Lesdites méthodes offrent une transfection de tissus plus efficace et localisée et sont bien adaptées à une thérapie génique effectuée chez des êtres humains.
EP03761219A 2002-06-24 2003-06-24 Methodes d'administration d'agents de therapie genique Withdrawn EP1532255A1 (fr)

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JP2008521575A (ja) * 2004-12-01 2008-06-26 ジェンザイム・コーポレイション 肝臓を標的とした遺伝物質の送達方法
CN102725400A (zh) * 2009-06-29 2012-10-10 麻省理工学院 制造人源化的非人类哺乳动物的方法
JP5922864B2 (ja) * 2010-06-15 2016-05-24 国立大学法人 新潟大学 時間−脈管内圧制御に基づく細胞内薬物送達システム及び細胞内薬物送達方法
EP2633880A1 (fr) 2010-10-25 2013-09-04 The Ritsumeikan Trust Procédé de fonctionnement d'un dispositif d'administration d'une substance à introduire, et procédé d'administration d'une substance à introduire
JP6188728B2 (ja) * 2012-02-07 2017-08-30 グローバル・バイオ・セラピューティクス・インコーポレイテッドＧｌｏｂａｌ Ｂｉｏ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 核酸送達の区画化方法ならびにその組成物および使用
CA2874316A1 (fr) 2012-05-03 2013-11-07 Indiana University Research And Technology Corporation Procedes hydrodynamiques pour administrer des fluides aux tissus renaux et materiaux et procedes associes
AU2014311994A1 (en) 2013-08-30 2016-04-21 Indiana University Research & Technology Corporation Hydrodynamic method and apparatus for delivering fluids to kidney tissues
US20210370037A1 (en) * 2018-04-27 2021-12-02 Seattle Children's Hospital D/B/A Seattle Children's Research Institute Ultrasound-mediated gene and drug delivery

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US6416510B1 (en) * 1997-03-13 2002-07-09 Biocardia, Inc. Drug delivery catheters that attach to tissue and methods for their use
US6290689B1 (en) * 1999-10-22 2001-09-18 Corazón Technologies, Inc. Catheter devices and methods for their use in the treatment of calcified vascular occlusions
US6135976A (en) * 1998-09-25 2000-10-24 Ekos Corporation Method, device and kit for performing gene therapy

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