Surgery – Miscellaneous – Methods
Reexamination Certificate
1998-03-27
2001-03-13
Nguyen, Dinh X. (Department: 3738)
Surgery
Miscellaneous
Methods
C604S020000, C604S890100, C604S048000, C606S002000, C607S089000
Reexamination Certificate
active
06199554
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a coordination of injury-inducing revascularization treatment and drug delivery to improve vascularization and increase gene expression.
The morbidity and mortality of ischemic heart disease are directly attributable to myocardial injury as a result of limited blood flow from atherosclerotic narrowing of the epicardial coronary arteries. Transmyocardial revasculaization (TMR) reduces the symptoms and morbidity of patients with end-stage ischemic heart disease (Fleischer et al., Ann. Thorac. Surg. 62: 1051-1058, 1996) IMP involves the use of a high-powered carbon dioxide (CO
2
) laser to create transmyocardial channels in regions of critically ischemic tissue. It has been speculated that these channels act as conduits to shunt oxygenated blood from the left ventricle into the extensive intramyocardial vascular plexus. However, an alternative mechanism proposed attributes the healing response to laser injury accompanied by neovascularization and increased collateral perfusion of thermally damaged tissue (Fleischer, supra).
SUMMARY OF THE INVENTION
The invention provides a method of enhancing injury-induced revascularization of a tissue as treatment of a disease, such as coronary artery disease. The method involves (i) creating injury in a tissue, e.g., as a result of mechanical, chemical, electromagnetic, or thermal perturbation, by making a channel in the tissue (e.g., muscle, such as cardiac muscle) by use of, e.g., a laser (a carbon dioxide, holmium:yttrium-aluminum garnet (HO:YAG), or thulium-holmium-chromium (THC-YAG) laser), an ultrasonic device, or a thermal probe, and (ii) injecting into the tissue a revascularization-promoting molecule (e.g., a protein, such as a pro-angiogenic factor, for example, vascular endothelial growth factor, fibroblast growth factor, platelet derived growth factor, insulin-like growth factor, epidermal growth factor, transforming growth factor, hepatocyte growth factor, proliferin, angiotropin, or angiopoietin) or a nucleic acid molecule (e.g., naked DNA) encoding a revascularization-promoting molecule.
Preferably, the track of the injection carried out using the method of the invention parallels the channel, and preferably the injection track is more than 1 mm and less than 4 mm from the channel. Also, the time between creating the channel and making the injection in the method preferably is less than 5.0 seconds, for example, less than 1.0 second, or less than 0.1 second. The number of the injections preferably is equal or greater than the number of the channels in the treated tissue.
Use of the method of the invention results in improvement of a condition of the disease to a greater degree than results from injury-induced revascularization treatment alone. For example, the condition can improve as a result of increased vascularization of tissue (e.g., muscle or connective tissue) affected by the disease (e.g., peripheral vascular disease or wound healing).
One example of a symptom that can be ameliorated using the method of the invention is abnormal left ventricular wall motion or abnormal myocardial function. Myocardial function can be assessed by measurements such as end-systolic elastance, the ratio of end systolic elastance, the volume of a (theoretically) completely unloaded ventricle, preload recruitable stroke work, comparison of ejection fraction and end diastolic volume, or the derivative of pressure divided by the derivative of time.
The cellular entry of a nucleic acid molecule administered to a tissue using the method of the invention can be facilitated by non-live viral mediated transfer. The nucleic acid molecule can be mixed with a lipid polyamine admixture. Also, the nucleic acid molecule can be operably linked to a promoter in a recombinant viral vector, such as a retrovirus, adeno-virus, adeno-associated virus, or lentivirus vector. A molecule administered using the method of the invention can undergo sustained release, e.g., as a result of encompassing the molecule within a polymeric microsphere, or linking the molecule to a complex, biodegradable molecule.
The invention also includes a method of increasing gene expression in a tissue. This method involves (i) creating tissue injury, e.g., as a result of mechanical, chemical, electromagnetic, or thermal perturbation, by making a channel in the tissue, e.g., by laser (a carbon dioxide, holmium:yttrium-aluminum garnet (HO:YAG), or thulium-holmium-chromium (THC-YAG) laser), ultrasonic, or thermal perturbation, and (ii) injecting into the tissue a nucleic acid molecule (e.g., naked DNA) containing the gene. This method results in increased expression of the gene compared to expression that results from injection of the nucleic acid molecule alone. Preferably, the track of the injection parallels the channel.
Cellular entry of a nucleic acid molecule using the method of the invention can be facilitated by non-live viral mediated transfer. A nucleic acid molecule can be mixed with a lipid polyamine admixture prior to administration. The nucleic acid molecule can be operably linked to a promoter in a recombinant viral vector, such as a retrovirus, adenovirus, adeno-associated virus, or lentivirus vector.
Also included in the invention is an apparatus for enhancing injury-induced revascularization of a tissue as a treatment of a disease. This apparatus includes, in operable linkage, a means for creating a channel in the tissue, and a means for injecting a biologically active compound into the tissue. The means for creating the channel in the tissue can include a source of directable heat, such as an aperture for a laser (e.g., a carbon dioxide laser gun) or an ultrasound probe, or a thermal probe.
The means for injecting the molecule into the tissue can include a cannula (e.g., a needle) in fluid communication with a fluid chamber (e.g., a syringe or a piece of tubing), and a fluid ejection means (e.g., a plunger or a pump). The cannula and the source of directable heat can be positioned in the apparatus so that the cannula and the pathway of the directable heat are parallel to one another, preferably about 1 mm to 4 mm apart.
In one embodiment of the apparatus of the invention, the aperture and one end of the cannula are positioned adjacent to one another when the apparatus is in a resting position. This apparatus also includes a projection means for projecting the cannula into the tissue, moving the apparatus into an active position, and for removing the cannula from the tissue, moving the apparatus into the resting position, when the aperture and the one end of the cannula are positioned near the surface of the tissue.
By “parallel” is meant that, for any given depth of the tissue, the distance between center line of the channel and the center line of the injection track left by the injecting needle, is constant to within 0.5 mm.
By “tissue injury” is meant cell damage that results from chemical, mechanical, electromagnetic or thermal perturbations.
By “pro-angiogenic” is meant stimulating growth of new blood vessels, with of either microvessels of less than 100 &mgr;M in diameter or larger and more muscular vessels.
By “revascularization-promoting” is meant stimulating the appearance of endothelial cells in the area of tissue injury.
One advantage of the present invention is the actual improvement of symptoms by increasing tissue vascularization This advantage is attributed to the careful placement of the protein or DNA injectate at a standard distance and parallel orientation with respect to the channel site. As a result of this careful placement, gene expression of the injected DNA is maximized, and the effect of the injected or expressed protein is also maximized in the area of tissue injury. In one preferred embodiment of the invention, the simultaneous delivery of the injectate and the formation of the channel facilitates the required placement precision, especially in actively contracting tissue such as a beating heart. As an additional advantage, the expression of any protein in a tissue can be enhanced by co-treatm
Cohn Lawrence H.
Dzau Victor
Mann Michael J.
Sayeed-Shah Umer
Clark & Elbing LLP
Nguyen Dinh X.
The Brigham and Women's Hospital Inc.
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