Hydrodynamic methods for delivering fluids to kidney tissues and related materials and methods
Inventors
Bacallao, Robert • Atkinson, Simon • Rhodes, George • CORRIDON, Peter
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-11911487-B2
Publication Date
2024-02-27
Expiration Date
2033-05-03
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Abstract
The present invention provides methods and materials useful delivering liquids, including liquids comprising nucleic acid molecules into cells. In particular, the present invention provides methods for delivering saline solution, exogenous compositions, and isolated vectors to kidney cells, using the renal vein as a guide and under hydrodynamic pressure. The delivery methods and materials herein are useful to research, prognose, ameliorate symptoms of kidney injury, and treat kidney pathologies.
Core Innovation
The invention provides methods and materials for delivering fluids, including nucleic acid molecules, into kidney cells of mammalian subjects using hydrodynamic delivery via the renal vein under retrograde pressure and temporary vein occlusion. This delivery achieves endogenous and exogenous molecule expression in renal cortical and medullary cells, including glomerular, tubular, and vascular cells, with increased efficiency, stability, and widespread expression. The methods enable gene transfer through the renal vein, improving cellular uptake and expression while limiting kidney injury.
The problem addressed is the difficulty in achieving efficient in vivo gene transfer to kidney cells due to intrinsic structural and permeability barriers, such as the glomerular filtration barrier which limits access to proximal tubule cells. Prior methods including arterial injection, pelvic catheter infusion, tail vein injection, and micropuncture have produced varied, limited, or localized gene expression with associated injury or insufficient distribution. There is a need for a reliable, efficient method to deliver nucleic acids and other fluids to multiple renal cell types with minimal injury for gene therapy research and treatment of kidney pathologies, including acute kidney injury (AKI).
This invention features a hydrodynamic retrograde injection via the renal vein combined with vascular clamping to transiently occlude blood flow, producing increased renal venous and peritubular capillary pressures to facilitate widespread passage and uptake of nucleic acids and macromolecules throughout the nephron segments and surrounding renal cells. The method achieves efficient, stable expression of various vectors including naked plasmids and adenovirus vectors with preserved renal function and minimal histological damage, surpassing previous delivery methods. It also has therapeutic potential in ameliorating symptoms and treating kidney diseases such as AKI and ischemia/reperfusion injury.
Claims Coverage
The patent contains three main independent claims covering methods for treating acute kidney injury through retrograde hydrodynamic injection into the renal vein using saline or fluid solutions.
Treatment of acute kidney injury by retrograde hydrodynamic renal vein injection of isotonic saline
A method involving occluding the renal vein of an acutely injured kidney, administering a therapeutically effective volume of isotonic saline via retrograde hydrodynamic injection between occlusion and kidney, increasing renal venous pressure during injection, waiting for pressure decrease before unoccluding the vein, and achieving normalized reduced serum creatinine levels post-treatment.
Treatment of acute kidney injury through delivery of fluid molecules to tubule lumens via retrograde hydrodynamic injection
A method occluding the renal vein of a kidney with acute injury, delivering fluid molecules retrogradely under elevated renal venous pressure to tubule lumens by injecting fluid between the occlusion and kidney, waiting for pressure normalization, then unoccluding the vein. This method results in decreased serum creatinine levels and is performed within a specific injection duration and fluid composition (saline).
General treatment method for acute kidney injury by retrograde hydrodynamic renal vein fluid injection
A method involving occlusion of the renal vein, administering a retrograde hydrodynamic injection of fluid into the occluded vein at a site between occlusion and kidney to increase venous pressure during injection, waiting for pressure drop before unoccluding the vein. This method does not specify fluid composition but embodies the hydrodynamic injection to treat acute kidney injury.
The independent claims cover methods to treat acute kidney injury by retrograde hydrodynamic injection of fluids, primarily isotonic saline, into an occluded renal vein to increase venous pressure, facilitate renal delivery of fluid to kidney cells and tubule lumens, and achieve therapeutic outcomes such as normalized serum creatinine levels. The claims emphasize occlusion timing, injection site, pressure monitoring, and fluid composition.
Stated Advantages
Provides relatively easy and reliable renal gene transfer with widespread expression compared to prior methods.
Achieves significant increases in nucleic acid molecule delivery efficiency and expression in multiple renal cell types including superficial and deep cortical and medullary regions.
Minimizes kidney injury and preserves renal structure and function after hydrodynamic injections.
Enables rapid delivery and monitoring of exogenous genes in live mammalian kidneys, facilitating research and potential clinical gene therapy.
Allows therapeutic fluid delivery that significantly lowers serum creatinine levels, indicating therapeutic benefit in acute kidney injury and ischemia/reperfusion injury.
Suitable for use with various mammalian subjects, including humans and laboratory animals, increasing versatility.
Documented Applications
Research tool to deliver exogenous genes and study normal and pathophysiological kidney conditions in live mammals.
Treatment and amelioration of acute kidney injury and related kidney pathologies via retrograde hydrodynamic infusion of saline and nucleic acids.
Delivery of therapeutic nucleic acid molecules to kidney cells for gene therapy to prevent or treat kidney diseases such as ischemia/reperfusion injury and other renal pathologies.
Monitoring transgene expression in vivo using intravital multiphoton and confocal microscopy to assess delivery efficiency and therapeutic outcomes.
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