Locally released growth factors to mediate motor recovery after stroke

Abstract

Methods of improving recovery of a mammal after an ischemic event (e.g., stroke) are provided. In various embodiments the methods involve administering a neural growth factor (e.g., BDNF) into the infarct (e.g., stroke) cavity in a biocompatible hydrogel formulation. In certain embodiments the hydrogel comprises a thiolated hyaluronan and a thiolated gelatin with an optional thiolated heparin.

1 : A method of improving recovery of a mammal after cerebral ischemia, said method comprising:
 administering a therapeutically effective amount of a brain growth factor to the infarct cavity in the brain of said mammal.   
     
     
         2 : The method of  claim 1 , wherein said administering comprises depositing a depot delivery system into said infarct cavity wherein said depot delivery system comprises said growth factor and provides sustained release of said growth factor over time, and/or said depot delivery system comprises cells that provide a sustained release of said brain growth factor. 
     
     
         3 : The method of  claim 2 , wherein said depot delivery system comprises a delivery system selected from the group consisting of a nanoparticle formulation, a hydrogel formulation, and an implantable mechanical delivery system. 
     
     
         4 : The method of  claim 3 , wherein said depot delivery system comprises a hydrogel comprising said growth factor and/or said cells. 
     
     
         5 : The method of  claim 4 , wherein said hydrogel comprises a biopolymer. 
     
     
         6 : The method of  claim 5 , wherein said hydrogel comprises one or more materials selected from the group consisting of hyaluronan, gelatin, thiol-modified hyaluronan, heparin, thiol-modified heparin, thiol-modified chondroitin sulfate, thiol-modified gelatin, a hyaluronan sodium salt, and an acrylated hyaluronic acid. 
     
     
         7 : The method of  claim 4 , wherein said hydrogel comprises a hyaluronan derivative and a gelatin derivative. 
     
     
         8 : The method of  claim 7 , wherein hyaluronan derivative comprises a thiolated hyaluronan. 
     
     
         9 : The method of  claim 7 , wherein said gelatin derivative comprises a thiolated gelatin. 
     
     
         10 : The method of  claim 8 , wherein said thiolated hyaluronan and thiolated gelatin are have each been thiol-modified using carbodiimide mediated hydrazide chemistry. 
     
     
         11 - 14 . (canceled) 
     
     
         15 : The method of  claim 7 , wherein said hydrogel further comprises a heparins or a heparin derivative. 
     
     
         16 : The method of  claim 15 , wherein said hydrogel comprises a thiol-modified heparin. 
     
     
         17 - 23 . (canceled) 
     
     
         24 : The method of  claim 2 , wherein said depot delivery system comprises a hydrogel containing said growth factor wherein said hydrogel provides sustained release of said growth factor. 
     
     
         25 : The method of  claim 24 , wherein said brain growth factor comprises one or more factors selected from the group consisting of BDNF, VEGF, IGF1, bFGF/FGF2, Ang1, Ang 2, BMP 2, BMP 3a, BMP 3b, BMP 4, BMP 5, BMP 6, BMP 7 (OP-1), CTNF, EGF, EPO, aFGF/FGF1, bFGF/FGF2, G-CSF, GDF10, GDF15, GDNF, GH, GM-CSF, HB-EGF, LIF, NGF, NT-3, NT 4/5, Osteopontin, PDGFaa, PDGFbb, PDGFab, PlGF, SCF, SDF1/CXCL12, and TGFβ. 
     
     
         26 - 63 . (canceled) 
     
     
         64 : The method of  claim 2 , wherein said depot delivery system comprises a hydrogel comprising cells that provide a sustained release of said brain growth factor. 
     
     
         65 : The method of  claim 64 , wherein said cells comprise stem cells or cells that have differentiated from stem cells in culture or after implantation into said mammal. 
     
     
         66 - 69 . (canceled) 
     
     
         70 : The method of  claim 64 , wherein said cells secrete one or more factors selected from the group consisting of BDNF, VEGF, IGF1, bFGF/FGF2, Ang1, Ang 2, BMP 2, BMP 3a, BMP 3b, BMP 4, BMP 5, BMP 6, BMP 7 (OP-1), CTNF, EGF, EPO, aFGF/FGF1, bFGF/FGF2, G-CSF, GDF10, GDF15, GDNF, GH, GM-CSF, HB-EGF, LIF, NGF, NT-3, NT 4/5, Osteopontin, PDGF-AA, PDGF-BB, PDGF-AB, PlGF, SCF, SDF1/CXCL12, and TGFβ. 
     
     
         71 - 109 . (canceled) 
     
     
         110 : The method of  claim 2 , wherein said administering comprises injecting said depot formulation into said ischemic cavity. 
     
     
         111 . (canceled) 
     
     
         112 : The method of  claim 2 , wherein:
 said depot delivery system is not administered within the first hour, or not administered within the first three hours, or not administered within the first 6 hours, or not administered within the first 12 hours, or not administered within the first 24 hours after the onset of the ischemic; and/or   said depot delivery system is administered after at least 24 hours after the onset of the ischemic event, or after at 2 days after the onset of the ischemic event, or after at least 3 days after the onset of the ischemic event, or after at least 4 or 5 days after the onset of the ischemic event, or after at least 7 days after the onset of the ischemic event; and/or   said depot delivery system is administered within one week of the onset of the ischemic event; and/or   said depot delivery system is administered after the subject is clinically stable from the ischemia and damage has substantially stopped progressing; and/or   said depot delivery system is initially administered after at least 3 days after the initial ischemic event; and/or   said depot delivery system is initially administered five or more days after the initial ischemic event; and/or   said depot delivery system is initially administered 5 or more days after the initial ischemic event up to about 1 year after the initial ischemic event.   
     
     
         113 - 118 . (canceled) 
     
     
         119 : The method of  claim 1 , wherein said mammal is a human. 
     
     
         120 . (canceled) 
     
     
         121 : A formulation for improving recovery of a mammal after cerebral ischemia, said formulation comprising:
 a hydrogel comprising one or more brain growth factors that, when placed in an infarct cavity in the brain of a mammal, provides sustained release of said growth factor over at least about one week; and/or   a hydrogel comprising cells that provide a sustained release of a brain growth factor over a period of at least about one week.   
     
     
         122 . (canceled) 
     
     
         123 : The formulation of  claim 121 , wherein said hydrogel comprises hyaluronan and gelatin and/or a hyaluronan derivative and a gelatin derivative. 
     
     
         124 - 132 . (canceled) 
     
     
         133 : The formulation of  claim 123 , wherein said hydrogel further comprises a heparin derivative. 
     
     
         134 - 142 . (canceled) 
     
     
         143 : The formulation of  claim 121 , wherein said brain growth factor comprises one or more factors selected from the group consisting of BDNF, VEGF, IGF1, bFGF/FGF2, Ang1, Ang 2, BMP 2, BMP 3a, BMP 3b, BMP 4, BMP 5, BMP 6, BMP 7 (OP-1), CTNF, EGF, EPO, aFGF/FGF1, bFGF/FGF2, G-CSF, GDF10, GDF15, GDNF, GH, GM-CSF, HB-EGF, LIF, NGF, NT-3, NT 4/5, Osteopontin, PDGFaa, PDGFbb, PDGFab, PlGF, SCF, SDF1/CXCL12, and TGFβ. 
     
     
         144 - 157 . (canceled) 
     
     
         158 : A method of improving recovery of a mammal after cerebral ischemia, said method comprising:
 administering an agent to said mammal that enhances AMPA signaling, wherein said agent is administered after a delay period from the onset of the ischemic event; and wherein said agent induces an increase in BDNF expression and/or activity.   
     
     
         159 - 176 . (canceled)