Perivascular mesenchymal precursor cell induced blood vessel formation

• US 20060286077A1
• Filed: 03/29/2004
• Published: 12/21/2006
• Est. Priority Date: 03/28/2003
• Status: Active Grant

• Current Assignee: Mesoblast, Inc. (Mesoblast Ltd.)
• Original Assignee: Mesoblast, Inc. (Mesoblast Ltd.)
• Inventors: Gronthos, Stan, Zannettino, Andrew
• Granted Patent: US 9,169,466 B2
• Time in Patent Office: Days
• US Class Current: 424/93.700
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/44 Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 2500/42 Organic phosphate, e.g. beta glycerophosphate
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2501/135 Platelet-derived growth factor [PDGF]
• CPC Class Codes: C12N 2501/165 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: C12N 2501/235 Leukemia inhibitory factor [LIF]
• CPC Class Codes: C12N 2501/39 Steroid hormones
• CPC Class Codes: C12N 2506/1392 from mesenchymal stem cells from other natural sources
• CPC Class Codes: C12N 5/0663 Bone marrow mesenchymal stem cells (BM-MSC)
• CPC Class Codes: C12N 5/0667 Adipose-derived stem cells [ADSC]; Adipose stromal stem cells
• CPC Class Codes: C12N 5/0668 Mesenchymal stem cells from other natural sources
• CPC Class Codes: C12N 5/0691 Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels

Abstract

Mesenchymal precursors cells have been isolated from perivascular niches from a range of tissues utilizing a perivascular marker. A new mesenchymal precursor cell phenotype is described characterized by the presence of the perivascular marker 3G5, and preferably also alpha smooth muscle actin together with early developmental markers such as STRO-1 and CD146/MUC18. The perivascular mesenchymal precursor cell is shown to induce neovascularisation and improvement in cardiac function. Suitable administration of preparations of the mesenchymal precursor cells are useful for treatment of cardiovascular diseases, cerebrovascular diseases and peripheral vascular diseases.

Claims

1-130. -130. (canceled)

131. A method of inducing the formation or repair of blood vessels in a target tissue of a patient, the method comprising the step of administering to said patient an effective amount of an enriched population of cells that express the marker STRO-1.

132. The method of claim 131 wherein the cells that express the marker STRO-1 are mesenchymal precursor cells (MPCs)

133. A method according to claim 131 wherein the repair of blood vessels results in arteriogenesis.

134. A method according to claim 131 wherein the repair of blood vessels results in the coating of vasculature with cells that express alpha-smooth muscle actin.

135. The method of claim 131 wherein the enriched population comprises at least 0.01% MPCs capable of forming a clonogenic colony.

136. The method of claim 131 wherein the enriched population comprises at least 1% MPCs capable of forming a clonogenic colony.

137. The method of claim 131 wherein the enriched population comprises at least 0.01% STRO-1bright MPCs.

138. The method of claim 131 wherein the enriched population comprises at least 0.1% STRO-1bright MPCs.

139. The method of claim 131 wherein the enriched population comprises at least 1% STRO-1bright MPCs.

140. The method of claim 131 wherein the enriched population of cells are additionally positive for one or more of the markers 3G5, MUC18/CD146 and alpha-smooth muscle actin.

141. The method of claim 131 wherein the enriched population of cells additionally co-express the marker VCAM-1.

142. The method of claims 131 wherein the enriched population of cells co-express any one or more of the markers selected from the group consisting of THY-1, VCAM-1, ICAM-1, PECAM-1, CD49a/CD49b/CD29, CD49c/CD29, CD49d/CD29, CD29, CD61, integrin beta5, 6-19, thrombomodulin, CD10, CD13, SCF, PDGF-R, EGF-R, IGF-1R, NGF-R, FGF-R and Leptin-R (STRO-2).

143. The method of claim 131 wherein the enriched population of cells are negative for markers of hematopoietic lineage such as CD34, CD45, and glycophorin-A.

144. The method of claim 131 wherein the enriched population of cells are derived from a tissue of the group consisting of adipose tissue, teeth, dental pulp, skin, liver, kidney, heart, retina, brain, hair follicles, intestine, lung, spleen, lymph node, thymus, pancreas, bone, ligament, bone marrow, tendon and skeletal muscle.

145. The method of claim 131 wherein the enriched population of cells are enriched from a perivascular niche within a vascularised tissue source.

146. The method of claim 131 wherein the enriched population of cells are derived from a perivascular niche within a non-haemopoietic vascularised tissue.

147. The method of claim 131 wherein the enriched population is cultured and/or expanded prior to administration.

148. The method of claim 147 wherein the cultured and/or expanded population comprises at least 0.01% MPCs capable of forming a clonogenic colony and differentiating to three or more mesenchymal tissue types.

149. The method of claim 147 wherein the cultured and/or expanded population comprises at least 1% MPCs capable of forming a clonogenic colony.

150. The method of claim 147 wherein the cultured and/or expanded population comprises at least 0.1% STRO-1bright MPCs.

151. The method of claim 147 wherein the cultured and/or expanded population comprises at least 1% STRO-1bright MPCs.

152. The method of claim 147 wherein the cultured and/or expanded population comprises at least 10% STRO-1bright MPCs.

153. The method of claim 147 wherein the cell population is expanded in the range of between 10² to 10⁴ fold.

154. The method of claim 131 wherein the enriched population of cells is administered by injection into the target tissue or close to the target tissue.

155. The method of claim 131 wherein the enriched population of cells is administered systemically or topically.

156. The method of claim 131 wherein at least about 10⁵ cells are administered.

157. The method of claim 131 further comprising coadministration of a substance to enhance formation of blood vessels.

158. The method of claim 131 wherein the patient is suffering from a disease associated with loss of cells expressing alpha smooth muscle actin from vasculature or perivascular tissue.

159. The method of claim 158 wherein the enriched population of cells is administered to target tissue containing abnormal blood vessels in need of repair, including abnormally proliferating, leaky, or aneurysmal blood vessels.

160. The method of claim 131 wherein the target tissue exhibits ischemia.

161. The method of claim 160 wherein said patient is in need of treatment for a condition selected from the group consisting of cerebrovascular ischemia, renal ischemia, pulmonary ischemia, limb ischemia, ischemic cardiomyopathy and myocardial ischemia.

162. The method of claim 131 wherein the target tissue is myocardium.

163. The method of claim 162 wherein the said subject suffers from a cardiovascular disease consisting of ischemic heart disease, coronary artery disease, acute myocardial infarction, congestive heart failure, cardiomyopathy, or angina.

164. The method of claim 162 wherein the cells are introduced into the body of the subject by localized injection, systemic injection, in a patch, or on a stent.

165. The method of claim 162 wherein the effective amount of the enriched population of MPC is administered by intracoronary catheter, or by intramyocardial, transepicardial or transendocardial injection.

166. The method of claim 162 wherein the enriched population of cells assemble into new blood vessel structures.

167. The method of claim 162 wherein the enriched population of cells induce formation of new blood vessel structures.

168. The method of claim 162 wherein the enriched population of cells induce formation of new cardiomyocytes.

169. The method of claim 162 wherein the enriched population of cells induce proliferation of resident cardiomyocytes.

170. The method of claim 131 wherein the cells are autologous.

171. The method of claim 131 wherein the cells are from an allogeneic source.

172. A method of inducing formation or repair of blood vessels, the method comprising the steps of culturing and/or expanding an enriched population of cells that express the marker STRO-1, and contacting said cultured and/or expanded cells to tissue in need of blood vessel formation or repair in order to generate new blood vessels or to repair existing blood vessels.

175. The method of claim 172 wherein the enriched population of cells comprises at least 0.01% MPCs capable of forming a clonogenic colony.

176. The method of claim 172 wherein the enriched population of cells comprises at least 1% MPCs capable of forming a clonogenic colony.

177. The method of claim 172 wherein the enriched population of cells comprise at least 0.01% STRO-1bright MPCs.

178. The method of claim 172 wherein the enriched population of cells comprise at least 0.1% STRO-1bright MPCs.

179. The method of claim 172 wherein the enriched population of cells comprise at least 1% STRO-1bright MPCs.

180. The method of claim 172 wherein the enriched population of cells are positive for any one or more of the markers 3G5, MUC18/CD146, and alpha-smooth muscle actin.

181. The method of claim 172 wherein the enriched population of cells additionally co-express the marker VCAM-1.

183. The method of claim 172 wherein the enriched population of cells are negative for hematopoietic lineage markers, including, but not limited to, CD34, CD45, and glycophorin-A.

184. The method of claim 172 wherein the population is enriched from a tissue of the group comprising, but not limited to skin, liver, kidney, heart, adipose tissue, teeth, dental pulp, retina, brain, hair follicles, intestine, lung, spleen, lymph node, thymus, pancreas, bone, ligament, bone marrow, tendon, and skeletal muscle.

185. The method of claim 172 wherein the enriched population of cells is isolated from a perivascular niche within a vascularised tissue source.

186. The method of claim 172 wherein the enriched population of cells is isolated from a perivascular niche within a non-haemopoietic vascularised tissue.

173. A method of inducing repair of blood vessels in a patient suffering from a disease associated with loss of cells expressing alpha smooth muscle actin from vasculature or perivascular tissue, the method comprising the steps of culturing and/or expanding an enriched population of cells that express the marker STRO-1, and contacting said cultured and/or expanded cells to tissue in need of blood vessel repair in order to result in a coating of blood vessels with alpha-smooth muscle actin-positive cells.

174. The method of claim 173 wherein the cultured and/or expanded population of cells is administered to target tissue containing abnormally proliferating, leaky, or aneurysmal blood vessels in need of repair.

182. The method of claim 173 wherein the enriched population of cells co-express any one or more of the markers selected from the group consisting of THY-1, VCAM-1, ICAM-1, PECAM-1, CD49a/CD49b/CD29, CD49c/CD29, CD49d/CD29, CD29, CD61, integrin beta5, 6-19, thrombomodulin, CD10, CD13, SCF, PDGF-R, EGF-R, IGF-1R, NGF-R, FGF-R, Leptin-R and (STRO-2).

187. The method of claim 187 wherein the cultured and/or expanded population comprises at least 0.01% MPCs capable of forming a clonogenic colony.

188. The method of claim 187 wherein the cultured and/or expanded population comprises at least 1% MPCs capable of forming a clonogenic colony.

189. The method of claim 187 wherein the cultured and/or expanded population comprises at least 0.1% STRO-1bright MPCs.

190. The method of claim 187 wherein the cultured and/or expanded population comprises at least 1% STRO-1bright MPCs.

191. The method of claim 187 wherein the cultured and/or expanded population comprises at least 10% STRO-1bright MPCs.