The patent's assignee for patent number 8623066 is
News editors obtained the following quote from the background information supplied by the inventors: "The present invention relates to apparatuses, systems and methods of treating a patient. Particularly, the present invention relates to treating medical conditions using cell therapy via body lumens. In some instances, the present invention relates to treating a blood vessel, such as in the treatment of heart disease and aneurysms.
"Heart disease continues to be a leading cause of death in
"Despite the overall initial success of these procedures, many patients undergoing these therapeutic procedures to clear blocked coronary arteries will suffer restenosis (re-blockage) at some point after the initial procedure. Such restenosis may be a manifestation of the general wound healing response or may be due to a variety of other factors.
"Thus, it would be desired to provide devices, systems and methods which would provide therapeutic benefits to injured or diseased tissue. Such benefits may include reduction of the incidence of restenosis, particularly in blood vessels treated for atherosclerosis. However such benefits may be applicable to any body lumen which suffers from occlusion and possible restenosis. In addition, such benefits may include a reduction in any initial injury induced by intervention, such as by stenting. At least some of these objectives will be met by the embodiments of the present invention.
"An aneurysm is the focal abnormal dilation of a blood vessel. The complications which arise from aneurysms can include rupture, embolization, fistularisation and symptoms related to pressure on surrounding structures. Aneurysms are commonly found in the abdominal aorta, being that part of the aorta which extends from the diaphragm to the point at which the aorta bifurcates into the common iliac arteries. These abdominal aortic aneurysms typically occur between the point at which the renal arteries branch from the aorta and the bifurcation of the aorta. When left untreated, an abdominal aortic aneurysm may eventually cause rupture of the aorta with ensuing fatal hemorrhaging in a very short time. High mortality associated with the rupture has led to the development of transabdominal surgical repair of abdominal aortic aneurysms.
"A clinical approach to aneurysm repair which is less invasive than conventional transabdominal surgery is known as endovascular grafting. Endovascular grafting typically involves the transluminal placement of a prosthetic arterial graft within the lumen of the artery. The graft may be attached to the internal surface of an arterial wall by means of attachment devices (often similar to expandable stents), one above the aneurysm and a second below the aneurysm. Such attachment devices permit fixation of a graft to the internal surface of an arterial wall without sewing.
"It would be desirable, to provide devices, systems and methods that improve the treatment of aneurysms, such as improving fixation of the graft, increased resistance to graft migration and leakage and/or improvements in the characteristics of the surrounding tissue once in place. At least some of these objectives will be met by the embodiments of the present invention.
"Methods have been developed for using pluripotent stem cells for therapeutic applications, including the delivery of therapeutic genes. Pluripotent stem cells appear to have the ability to differentiate into a number of different cell types, including neurons, cardiomyocytes, skeletal muscle, smooth muscle and pancreatic beta cells, to name a few, that are involved in the pathogenesis of many human diseases, such as atherosclerosis, diabetes, hypertension and various others. However, current methods have limitations which preclude the successful use of such pluripotent stem cells in treating various medical conditions.
"To begin, a stem cell per se exhibits almost no target tissue selectivity. As such, if stem cells are simply introduced to target tissues by current methods, such as intravenously or by direct injection, a safety concern is the risk that the cells will differentiate into a non-target cell type and disrupt the normal functions in the target tissues. At worst, this may result in tumorigenesis and/or patient mortality. A possible solution is to use stem cells which have been triggered to becoming the target cell type, i.e. progenitor cell types such as smooth muscle progenitor cells. Since these stem-cell derived progenitor cells have started onto the differentiation pathway sufficiently to be 'committed' to becoming the desired cell type, there is reduced risk of tumorigenesis or differentiation into an undesired cell type. The drawback to this approach (i.e. the use of progenitor cells) is that the engraftment efficiency is usually inversely related to the extent of cell differentiation. Thus, while the use of stem-cell-derived progenitor cells may reduce or eliminate safety concerns, the fact that the progenitor cells are further down the differentiation pathway as compared to pluripotent stem cells means that their engraftment efficiency is reduced, and this will in turn reduce the likelihood of a clinical benefit.
"Alternatively, differentiated somatic cells have been used for cell-based therapies. However, these applications have also been limited by the lack of methods to provide efficient engraftment as described above.
"Thus, it would be desirable to provide devices, systems and methods that will deliver therapeutic cells directly to the target site, such that regardless of the extent to which these cells have differentiated, their engraftment into the target site will be significantly improved. At least some of these objectives will be met by the embodiments of the present invention.
"Interest has developed in using non-autologous cells for cell-based therapies, particularly non-autologous embryonic stem cells. Embryonic stem cells may have properties, such as pluripotentiality and infinite replicative life span, that are not obtainable with autologous somatic stem cells. In addition, various non-human cells may be used in the treatment of human diseases, for example, porcine pancreatic beta cells for treatment of diabetes. However, non-autologous and non-human cells are attacked by the patient's immune system, thus limiting their long term efficacy and viability.
"Thus, it would be desirable to provide devices, systems and methods that allow the delivery of non-autologous cells to a desired tissue site while simultaneously isolating them from the patient's immune system. This would reduce or prevent any immunologic rejection of the cells. At least some of these objectives will be met by the embodiments of the present invention."
As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "The present invention provides devices, systems and methods for the localized delivery of cells which provide a therapeutic benefit. The cells may include but are not limited to autologous stem cells. Localized delivery is achieved with the use of a stent-like expandable body seeded with cells which is positioned within a body lumen. The expandable body is expanded to contact at least a portion of the inner walls of the body lumen and the cells and/or cellular products are delivered to the surrounding tissue. The therapeutic benefit provided is dependent on the type of cells used and the features of the expandable body, to name a few.
"In a first aspect of the present invention, the expandable body may take the form of any of a variety of stents used for placement within body lumens, such as blood vessels. For example, the expandable body may comprise a conventional stent used to treat coronary occlusions, such as described by U.S. Pat. Nos. 6,540,775, 6,113,621, and 4,776,337, each of which is incorporated by reference herein for all purposes. Or, the expandable body may comprise a conventional stent graft used to treat aneurysms, particularly abdominal aortic aneurysms, such as described by U.S. Pat. Nos. 5,824,039 and 5,693,084, each of which is incorporated by reference herein for all purposes.
"In other embodiments, the expandable body comprises a device such as provided by Reed et al. (U.S. Pat. No. 6,197,013), incorporated by reference herein for all purposes. The Reed et al. devices include arrays of micromechanical probes present on the surface of the devices which penetrate the body lumen wall and allow for efficient transport of therapeutic agents, such as cells, into the wall. In the specific example of blood vessels, delivery can be effected directly to at least the medial layer of the vessel wall.
"In still other embodiments, the expandable body comprises a device having deployable microstructures, such as provided by U.S. Provisional Patent Application No. 60/395,180, U.S. Provisional Patent Application No. 60/421,404, and PCT Application No. PCT/US03/21754, the full disclosures of which are hereby incorporated by reference for all purposes. The microstructures are formed in or attached to the expandable body in a low profile fashion suitable for atraumatic introduction to the body lumen with the use of a catheter or other suitable device. Each microstructure has an end which is attached to the expandable body and a free end. Once the apparatus is positioned within the body lumen in a desired location, the body is expanded and the microstructures deployed to a position wherein the free ends project radially outwardly. The free ends of the deployed microstructures then penetrate the lumen wall by continued expansion of the body. Additionally, a therapeutic agent, such as cells, may be delivered to the lumen wall by the microstructures. When the expandable body comprises a stent, the mechanism may be left in place, the microstructures providing anchoring and sealing against the lumen wall.
"In yet other embodiments, the expandable body comprises any of the devices for treating aneurysms described in U.S. Provisional Patent Application No. 60/421,350, U.S. Provisional Patent Application No. 60/428,803 and PCT Application No. PCT/US03/21611, the full disclosures of which are hereby incorporated by reference for all purposes. These devices include a tube which is held in place within the vasculature by at least one expandable body having at least one microstructure. The microstructures are attached to the expandable body in a low profile fashion suitable for atraumatic introduction to the vasculature with the use of a catheter or other suitable device. Each microstructure has an end which is attached to the expandable body and a free end. Once the apparatus is positioned within the vasculature in the desired location, the microstructures are deployed so that the free ends project radially outwardly. The free ends of the deployed microstructures then penetrate the blood vessel wall by continued expansion of the body, holding the tube in place.
"It may be appreciated that the expandable body may take the form of any device which is expandable within a body lumen to provide localized delivery of cells and/or cellular products to the body lumen. Various body lumens are found in but are not limited to the vascular system, the pulmonary system, the gastro-intestinal tract, the urinary tract and the reproductive system.
"It may be further appreciated that the surface of the expandable body may be porous to allow for a greater retention of therapeutic agents, cells or other substances that may have direct or indirect therapeutic benefits, such as matrix components, growth factors and/or combinations thereof. These substances may promote wound healing or tissue/organ regeneration or repair by augmenting the function of the patient's existing cells or tissues. Some embodiments of such a porous surface are obtained by means of a de-alloying method, preferred embodiments of which have been described in U.S. Provisional Patent Application No. 60/426,106 filed on
"In a second aspect of the present invention, the cells seeded on the expandable body may be comprised of any cells which provide a therapeutic benefit to the body lumen. Examples of such cells include endothelial cells, pancreatic beta cells, myofibroblasts, cardiac myocytes, skeletal muscle satellite cells, smooth muscle cells, dendritic cells, epithelial cells, multi-potential somatic stem cells and derivatives thereof, embryonic stem cells and derivatives thereof, neuronal cells, glial cells, hepatocytes, and various endocrine cells (e.g. thyroid, parathyroid, adrenal cortex), to name a few.
"In some embodiments, genetically modified cells are used to over-express a therapeutic gene. In preferred embodiments, genetically modified smooth muscle cells (SMC) are used. This is because a large number of major human diseases, including coronary artery disease, hypertension, and asthma are associated with abnormal function of SMCs. In addition, SMC dysfunction also contributes to numerous other human health problems including vascular aneurysms, and reproductive, bladder and gastrointestinal disorders. Therefore, a therapeutic effect can be achieved by delivering SMCs which have been genetically modified to over express a therapeutic agent, thereby reducing or eliminating the physiological consequences caused by SMC dysfunction.
"Although the present invention relates to the use of a plurality of cell types and sources, one preferred embodiment uses genetically modified stem cells or cells derived therefrom. Stem cells exhibit a virtually infinite replicative lifespan which is beneficial for carrying out genetic engineering methods. Such a lifespan is also beneficial for being able to generate sufficient numbers of cells for clinical applications. This is particularly useful since a patient's own stem cells may often be available in very limited supply, at least without major surgery or patient risk. In contrast, use of somatic differentiated cell populations are limited in that these cells can only undergo a relatively small number of population doublings before senescing.
"One preferred embodiment of the present invention is to employ stem cell derived smooth muscle progenitor cells produced using methods described in WO 02/074925, incorporated herein by reference for all purposes. These smooth muscle progenitor cells have been isolated and purified by transforming a population of pluripotent somatic or embryonic stem cells with a DNA construct comprising a smooth muscle specific promoter operably linked to a selectable marker gene.
"Delivery of therapeutic genes for treatment of SMC related diseases such as atherosclerosis, asthma, hypertension, etc. In this embodiment of the technology, stem cell derived SM tissues or cells would be genetically engineered to express a desired therapeutic gene or agent and surgically implanted into a desired treatment site in vivo. An example would be implantation of stem cell derived vascular SMC that express high levels of NO synthase into coronary vessels as a means of treating coronary atherosclerosis or re-stenosis.
"A major limitation in using these stem cell derived smooth muscle progenitor cells with conventional delivery methods is that the conventional delivery methods do not provide effective engraftment of the cells into the desired tissue site while at the same time reducing or eliminating the risks of delivery to non-target sites. As mentioned, the engraftment potential is highest for undifferentiated cells, however undifferentiated cells pose the greatest risk for tumorigenesis or other undesired side effects. Therefore, a balance between these risks and benefits is desired. Such a balance may be achieved by the use of expandable bodies having micromechanical probes, such as provided by Reed et al. (U.S. Pat. No. 6,197,013), or expandable bodies having deployable microstructures as described above. In this preferred embodiment, the cells are seeded onto the expandable body and delivered directly to specific locations, particularly within the wall of a body lumen. The cells are mechanically embedded into and/or held against the wall of the body lumen which improves engraftment of the cells into the target tissue. This process may be further aided by use of the porous coating to deliver agents that promote engraftment as well as other desired properties of the cells.
"In preferred embodiments, genetically modified autologous SMC, adult or embryonic stem cell derived SMC or SMC progenitor cells isolated from the patient's own somatic stem cells are used. In some embodiments, SMC progenitor cells as described in PCT/US02/08402, incorporated herein for all purposes, may be used. Any of these cells may be modified to over-express a possible therapeutic gene, such as endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS). Nitric oxide (NO) has many actions that could be beneficial to the vascular system, particularly following vascular injury. These include inhibition of platelet deposition and leukocyte adherence, inhibition of vascular smooth muscle cell proliferation and migration, inhibition of endothelial cell apoptosis, stimulation of endothelial cell growth, and vasodilation. Furthermore, inadequate NO production at sites of injury has been shown to contribute to vascular occlusive diseases including atherosclerosis and restenosis following angioplasty, endarterectomy, cardiac bypass surgery, or peripheral vascular bypass surgery. Local delivery of NO to a particular site may be achieved through transfer of an NOS gene, such as eNOS, iNOS, or nNOS, to the site by incorporation into the cells of the cell-seeded expandable body of the present invention. By delivering NOS gene expressing cells to a specific site, NO will be produced at that site without systemic effects. In addition, a porous surface on the expandable body, as described previously, may be used to release co-factors that are known to enhance the biological activity of NOS/NO.
"Alternative genes that might be expressed to confer a therapeutic benefit include TGF.sub..beta.1, which has anti-inflammatory properties and which also has been shown to inhibit SMC growth, promote differentiation, and enhance production of extracellular matrix components. Other possibilities include cytokines IL-4, IL-10 or IL-13 whose anti-inflammatory properties may promote wound repair or regeneration and/or reduced restenosis.
"It may be appreciated that genetic modification such as described above may be applied to cells other than SMCs, and these cells may also be used with the cell-seeded expandable body of the present invention. In addition, the methods provided in WO 02/074925, exemplified for the isolation of SMC and smooth muscle progenitor cells, are readily adaptable to the production of any desired cell type by replacing the SMC specific/selective promoter/enhancer of the reporter gene construct with an appropriate promoter regulatory element that is selective/specific for the cell type of interest. Examples include the use of promoter/enhancers specific for cardiac myocytes, endothelial cells and neurons. As an example, cells used in the present invention may be comprised of progenitor cells derived by a method comprising the steps of providing a population of cells comprising totipotent or pluripotent cells, transfecting the population of cells with a nucleic acid sequence comprising a smooth muscle cell specific promoter/enhancer operably linked to a marker, inducing the population of cells to become smooth muscle cells and identifying the smooth muscle progenitor cells based on the expression of the marker.
"In other embodiments, cells which have not been genetically modified to over-express a possible therapeutic gene, referred to herein as 'unmodified cells', are used. Such cells may be used to augment tissue repair and regeneration. For example, when unmodified autologous SMC, stem cell derived SMC or SMC progenitor cells are used, proliferation of the SMCs and/or associated production of extracellular matrix components including collagen and elastin can rebuild blood vessels. The blood vessels may have been damaged due to traumatic injury, such as by an accident, major reconstructive surgery, or repair of a congenital vascular defect. The SMCs can also be used to rebuild blood vessels which suffer from aneurysms, a progressive vascular abnormality associated with degeneration and dissection of the blood vessel wall and SMC hypocellularity. They may be caused by many factors including extensive atherosclerotic disease, a congenital vascular defect, or mutations in genes important for determining the tensile strength of blood vessels, such as in the case of Marfan's Syndrome which is the result of mutations in the fibrillin gene. In addition, a porous surface on the expandable body may be employed to deliver agents that enhance the desired properties of the unmodified cells. For example, TGF.sub..beta.1 may be used since it is known to dramatically enhance matrix production, and/or PDGF BB may be used to promote proliferation of progenitor cells provided on the device as well as recruitment of resident cells that could aid in the repair process.
"When the cell-seeded expandable bodies of the present invention are used to treat an aneurysm, the expandable bodies anchor a tube or graft to the vessel walls surrounding an aneurysm. SMCs may be delivered to the vessel walls to increase anchorage of the tube and reduce migration of the tube along the blood vessel. Such migration could lead to leakage, exposure of the aneurysm and damage to the blood vessel, to name a few. In addition, the improved anchorage may also prevent apparent migration of the apparatus which occurs when the aneurysmal sac grows in size and as such encroaches upon the ends of the apparatus. This results in a reduction of the distance between the terminus of the apparatus and the aneurysm which is the same effect as migration. Thus, the SMCs help maintain intimate contact between the apparatus and the vessel wall and prevent aneurysmal sac growth. The SMCs can also be delivered to the blood vessel lumen, the blood vessel walls and/or the outer surface of the blood vessel to encourage tissue regrowth or extra-cellular matrix formation. The SMCs may also be delivered to the aneurysmal sac. This may allow for tissue regrowth within the sac, strengthening the tissue within the aneurysmal walls. In addition, as noted above, a porous surface on the device may be employed to deliver agents to enhance the repair or regenerative process.
"SMCs may also be employed in reconstructive surgery of the gastrointestinal tract, urinary tract, or other tissues in which SMC are a predominant cell type. Other cell types may also be used to rebuild other types of tissues. For example, autologous stem cell derived cell types may be used to enhance wound healing, bone repair, musculo-skeletal repair following traumatic injury or disease, tissue engineering, and replacement of degenerative or senescent cells, to name a few."
For additional information on this patent, see: Looi, Kareen; Owens,
Keywords for this news article include: Tissue Engineering, Biomedical Engineering, Biomedicine, Pharmaceuticals, Drugs, Surgery, Arteries, Genetics, Pancreas, Synthase, Angiology, Chemicals, Chemistry, Treatment, Cardiology, Immunology, Restenosis, Angioplasty, Hypertension, Muscle Cells, Nitric Oxide, Therapeutics, Blood Vessels, Cardio Device, Heart Disease.
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