Methods and compositions for delivery of exogenous factors to nervious system sites

Abstract

The present invention relates to treatment methods and methods for sustained delivery of one or more exogenous factors to desired nervous system sites. In certain embodiments, the invention relates to the use of biodegradable microspheres to deliver exogenous factors, such as the morphogenic factor, sonic hedgehog (Shh), to the site of spinal cord injury. In certain embodiments, the Shh-releasing microspheres are administered together with stem cells, which may be spinal cord neural stem cells. In certain embodiments, the invention relates to regrowth of neural cells in both the central and peripheral nervous systems.

1 . A method for treating a nervous system injury in a mammal comprising administering to a mammal at a site of nervous system injury an effective amount for treating the nervous system injury of a pharmaceutical formulation comprising at least one exogenous growth factor, said pharmaceutical formulation providing sustained delivery of the at least one exogenous growth factor for at least about 7 days. 
     
     
         2 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         3 . The method of  claim 1 , wherein the nervous system injury is selected from the group consisting of spinal cord injury, amyotrophic lateral sclerosis (ALS), peripheral nerve injury, and spinal nerve injury. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical formulation further comprises an effective amount of stem cells, wherein the amount of stem cells in combination with said at least one exogenous growth factor is effective for treating a nervous system injury. 
     
     
         6 . The method of  claim 1 , wherein the at least one exogenous growth factor is selected from the group consisting of Nerve Growth Factor (NGF), Glial Cell Line-Derived Growth Factor (GDNF), Neurotrophin (NT) 3, NT 4/5, NT 6, Ciliary Neurotrophic Growth Factor (CNTF), Leukemia Inhibitory Factor (LIF), Interleukin 6 (IL6), Interleukin 11 (IL11), Cardiotrophin 1, a growth factor hormone, basic fibroblast growth factor (bFGF), insulin-related growth factor (IGF-1), brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and sonic hedgehog (Shh). 
     
     
         7 . The method of  claim 5 , wherein the stem cells are neural stem cells. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical formulation is administered by at least one injection at the site of nervous system injury. 
     
     
         9 . The method of  claim 8 , wherein a second injection is administered at a site rostral to the site of nervous system injury. 
     
     
         10 . The method of  claim 1 , wherein the stem cells are endothelial-expanded stem cells. 
     
     
         11 . The method of  claim 10 , wherein the endothelial-expanded stem cells are pre-treated with sonic hedgehog. 
     
     
         12 . The method of  claim 10 , wherein the endothelial-expanded stem cells are pre-treated with sonic hedgehog and retinoic acid. 
     
     
         13 . A method for increasing neural cell growth or regenerating neural cells in a mammal which comprises administering, to a mammal at a site at which it is desired to increase neural cell growth or regenerate neural cells, an effective amount for increasing neural cell growth or regenerating neuronal cells of a sustained release pharmaceutical formulation comprising at least one exogenous growth factor, said pharmaceutical formulation continuously delivering the at least one exogenous growth factor for at least about 7 days. 
     
     
         14 . The method of  claim 13 , wherein the mammal is a human. 
     
     
         15 . The method of  claim 13 , wherein the neural cell is selected from the group consisting of neurons, glial cells, and progenitor cells. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 13 , wherein the pharmaceutical formulation further comprises an effective amount of stem cells, wherein said amount in combination with said at least one exogenous growth factor is effective for increasing neural cell growth or regenerating neural cells. 
     
     
         18 . The method of  claim 13 , wherein the at least one exogenous growth factor is selected from the group consisting of Nerve Growth Factor (NGF), Glial Cell Line-Derived Growth Factor (GDNF), Neurotrophin (NT) 3, NT 4/5, NT 6, Ciliary Neurotrophic Growth Factor (CNTF), Leukemia Inhibitory Factor (LIF), Interleukin 6 (IL6), Interleukin 11 (IL11), Cardiotrophin 1, a growth factor hormone, basic fibroblast growth factor (bFGF), insulin-related growth factor (IGF-1), brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and sonic hedgehog (Shh). 
     
     
         19 . The method of  claim 17 , wherein the stem cells are neural stem cells. 
     
     
         20 . The method of  claim 13 , which comprises administering at least one injection of the pharmaceutical formulation at the site at which it is desired to increase neural cell growth or regenerate neural cells. 
     
     
         21 . The method of  claim 20 , which comprises administering a second injection of the pharmaceutical formulation at the site at which it is desired to increase neural cell growth or regenerate neural cells. 
     
     
         22 . The method of  claim 13 , wherein the stem cells are endothelial-expanded stem cells. 
     
     
         23 . The method of  claim 22 , wherein the endothelial-expanded stem cells are pre-treated with sonic hedgehog. 
     
     
         24 . The method of  claim 22 , which comprises pre-treating endothelial expanded stem cells with sonic hedgehog and retinoic acid. 
     
     
         25 - 32 . (canceled)