Long lasting drug formulations

Abstract

The present invention is directed to long-lasting therapeutic formulations and their methods of use wherein the formulation comprises a genetically modified micro-organ that comprises a vector which comprises a nucleic acid sequence operably linked to one or more regulatory sequences, wherein the nucleic acid sequence encodes a therapeutic polypeptide, such as erythropoietin or interferon alpha.

1 .- 105 . (canceled) 
     
     
         106 . A method of treating anemia in a human subject in need thereof comprising the steps of:
 (a) providing at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin, wherein the at least one dermal micro-organ is an intact explant of living tissue that maintains the micro-architecture and the three dimensional structure of the dermal tissue from which it was derived and wherein the dermal micro-organ lacks a complete epidermal layer, wherein the genetic modification of the dermal micro-organ comprises using a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences; and   (b) implanting the at least one dermal micro-organ in said human subject, wherein the method increases or maintains hemoglobin levels in said subject and the increased or maintained hemoglobin levels are maintained for at least three months.   
     
     
         107 . The method of  claim 106 , further comprising determining in vivo erythropoietin serum levels in said subject before and/or after implanting. 
     
     
         108 . The method of  claim 106 , further comprising determining erythropoietin secretion levels of the at least one dermal micro-organ in vitro before implanting. 
     
     
         109 . The method of  claim 106 , wherein expression of erythropoietin is optimized for increased erythropoietin expression levels, increased duration of expression or a combination thereof. 
     
     
         110 . The method of  claim 106 , wherein the increased hemoglobin levels are maintained for at least 1 year. 
     
     
         111 . The method of  claim 106 , further comprising implanting to the subject at a later date an additional at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin. 
     
     
         112 . The method of  claim 106 , wherein the implanting is subcutaneous or intradermal. 
     
     
         113 . The method of  claim 106 , wherein the subject is suffering from chronic kidney disease (CKD). 
     
     
         114 . The method of  claim 106 , wherein the subject is suffering from end stage renal disease. 
     
     
         115 . The method of  claim 106 , wherein the subject is suffering from renal failure. 
     
     
         116 . The method of  claim 106 , wherein the nucleic acid sequence encoding erythropoietin comprises a sequence at least 95% identical to SEQ ID NO:1. 
     
     
         117 . A method of increasing or maintaining hemoglobin levels in a human subject over a sustained period of time comprising the steps of:
 (a) providing at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin, wherein said dermal micro-organ is an intact explant of living tissue that maintains the micro-architecture and the three dimensional structure of the dermal tissue from which it was derived and wherein the dermal micro-organ lacks a complete epidermal layer, wherein said genetic modification of said dermal micro-organ comprises using a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences; and   (b) implanting said at least one genetically modified autologous dermal micro-organ in said human subject at an effective dosage,   
       wherein said increased or maintained hemoglobin levels are maintained for at least three months. 
     
     
         118 . The method of  claim 117 , further comprising determining in vivo erythropoietin serum levels in said subject before and/or after implanting. 
     
     
         119 . The method of  claim 117 , further comprising determining erythropoietin secretion levels of the at least one dermal micro-organ in vitro before implanting. 
     
     
         120 . The method of  claim 117 , wherein expression of erythropoietin is optimized for increased erythropoietin expression levels, increased duration of expression or a combination thereof. 
     
     
         121 . The method of  claim 117 , wherein the increased hemoglobin levels are maintained for at least 1 year. 
     
     
         122 . The method of  claim 117 , further comprising implanting to the subject at a later date an additional at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin. 
     
     
         123 . The method of  claim 117 , wherein the implanting is subcutaneous or intradermal. 
     
     
         124 . The method of  claim 117 , wherein the subject is suffering from chronic kidney disease (CKD). 
     
     
         125 . The method of  claim 117 , wherein the subject is suffering from end stage renal disease. 
     
     
         126 . The method of  claim 117 , wherein the subject is suffering from renal failure. 
     
     
         127 . The method of  claim 117 , wherein the nucleic acid sequence encoding erythropoietin comprises a sequence at least 95% identical to SEQ ID NO:1.