Method for stem cell differentiation in vivo by delivery of morphogenes with mesoporous silica and corresponding pharmceutical active ingredients

Abstract

A pharmaceutical active ingredient for cell differentiation to alleviate cell and cell-related deficiencies in mammals comprising porous silica containing a releasable agent capable of contributing to a cell environment conducive for stem cell differentiation in co-implanted stem cells and/or in endogenous stem cells.

1 . A pharmaceutical active ingredient for cell differentiation to alleviate cell and cell-related deficiencies in mammals comprising porous silica containing a releasable agent capable of contributing to a cell environment conducive for stem cell differentiation in co-implanted stem cells and/or in endogenous stem cells. 
     
     
         2 . A pharmaceutical active ingredient as described in  claim 1 , wherein said porous silica has a surface area higher than 200 m 2 /g and a pore size between 1.5-50 nm. 
     
     
         3 . A pharmaceutical active ingredient as described in  claim 1  wherein said porous silica has average particle size and/or sizes in the range between 50-5000 nm. 
     
     
         4 . A pharmaceutical active ingredient as described in  claim 1  wherein the porous silica particles have a particle shape comprising of spheres or rod-shaped particles. 
     
     
         5 . A pharmaceutical active ingredient as described in  claim 4  wherein the porous silica particles are in the form of substantially spherical particles having a size range of 200-500 nm. 
     
     
         6 . A pharmaceutical active ingredient according to  claim 1 , wherein said releasable agent capable of contributing to a cell environment conducive for stem cell differentiation in co-implanted stem cells and/or in endogenous stem cells is 1-60% of the total weight of the pharmaceutical active ingredient. 
     
     
         7 . A pharmaceutical active ingredient according to  claim 6 , wherein said releasable agent capable of contributing to a cell environment conducive for stem cell differentiation in co-implanted stem cells and/or in endogenous stem cells is 1-45 wt % of the total weight of the pharmaceutical active ingredient. 
     
     
         8 . A pharmaceutical active ingredient according to  claim 1 , wherein said releasable agents is capable of forcing co-implanted cells to become postmitotic, in case when transplanted cells are or may be pre-mitotic. 
     
     
         9 . A pharmaceutical active ingredient according to  claim 1 , wherein said co-implanted stem cells are selected from the group consisting of regional stem cells, embryonic stem (ES) cells, neural crest stem cells, neural stem cells from brain and spinal cord, mesenchymal stem cells, endothelial stem cells, endodermal stem cells, induced pluripotent stem (iPS) cells. 
     
     
         10 . A pharmaceutical active ingredient according to  claim 1 , wherein said releasable agent is selected from the group consisting of secreted growth factors and morphogens, including, but not limited to fibroblast growth factors (FGFs), Wnts, transforming growth factor (TGF)-beta family members, Hedgehog (hh) proteins, retinoic acid, vascular endothelial growth factor (VEGF), Dickkopf (Dick)-1, insulin, Activin, SDF-1/CXCL12), pleiotrophin (PTN), insulin-like growth factor 2 (IGF2), ephrin B1 (EFNB1), cAMP, Semaphorins, Slits, Netrins, NCAM, L1-CAM, NGF, BDNF, NT3, NT4/5, GDNF, Artemin, Persephin, CNTF, LIF, Oncostatin M, Cardiotrophin 1, CDNF/MANF. 
     
     
         11 . A pharmaceutical active ingredient according  claim 1 , wherein the activity of the porous silica containing releasable agents is able to provide simultaneous or independent effects on co-implanted/endogenous stem cells. 
     
     
         12 . A delivery system for delivery of a pharmaceutical active ingredient in mammals, comprising a pharmaceutical active ingredient according to  claim 1 , and stem cells. 
     
     
         13 . A delivery system for delivery of a pharmaceutical active ingredient in mammals according to  claim 12 , wherein said stem cells are selected from the group consisting of regional stem cells, embryonic stem (ES) cells, neural crest stem cells, neural stem cells from brain and spinal cord, mesenchymal stem cells, endothelial stem cells, endodermal stem cells, induced pluripotent stem (iPS) cells. 
     
     
         14 . A method of treating cell and cell-related deficiencies in a mammal, comprising the consecutive steps:
 (a) preparation of a pharmaceutical active ingredient for cell differentiation, long-term survival and axonal growth to alleviate cell and cell-related deficiencies in mammals comprising porous silica containing a releasable agent capable of delivering factors conducive for differentiation/survival/tumor suppression, axonal growth and optionally additional suppressor(s) or activator(s) with the cell;   (b) transplantation of said cells to said mammal, and   (c) activation or suppression of releasable factors (s) by regulation of pore size, surface chemistry, lipophilicity and dissolving properties of the porous silica in co-implanted or endogenous stem cells.   
     
     
         15 . The method according to  claim 14 , wherein the cells for implantation are selected from the group consisting of regional stem cells, embryonic (ES) stem cells, neural crest stem cells, neural stem cells from brain and spinal cord, mesenchymal stem cells, endothelial stem cells, endodermal stem cells, iPS cells. 
     
     
         16 . The method according to  claim 14 , wherein the releasable agents are selected from the group consisting of secreted growth factors or their peptide mimetic analogs, guidance molecules and morphogens, including, but not limited to, fibroblast growth factors (FGFs), Wnts, transforming growth factor (TGF)-beta family members, and Hedgehog (hh) proteins, retinoic acid, VEGF, Dkk1, insulin, Activin, SDF-1/CXCL12), pleiotrophin (PTN), insulin-like growth factor 2 (IGF2), ephrin B1 (EFNB1), cAMP, Semaphorins, Slits, Netrins, NCAM, L1-CAM, NGF, BDNF, NT3, NT4/5, GDNF, Artemin, Persephin, CNTF, LIF, Oncostatin M, Cardiotrophin 1, CDNF/MANF. 
     
     
         17 . The method according to  claim 14  for treating degenerative disorders including but not limited to Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Spinal muscular atrophy, Stroke, Traumatic brain or spinal cord injury, Multiple sclerosis, Diabetes type 1 and 2, Muscular dystrophies, Cardiomyopathies, and Age-related macular degeneration. 
     
     
         18 . A pharmaceutical active ingredient as described in  claim 2  wherein said porous silica has average particle size and/or sizes in the range between 50-5000 nm. 
     
     
         19 . A pharmaceutical active ingredient as described in  claim 2  wherein the porous silica particles have a particle shape comprising of spheres or rod-shaped particles. 
     
     
         20 . A pharmaceutical active ingredient as described in  claim 3  wherein the porous silica particles have a particle shape comprising of spheres or rod-shaped particles.