Use of hyaluronan in gene therapy

Abstract

A method of treating a human suffering a disease or condition caused by a gene, cDNA or RNA-DNA oligonucleotide or RNA-DNA oligonucleotide hybrids or messenger RNA implicated in a disease or condition involving cells that express hyaluronic acid receptors is provided, the method comprising administering to such human, an effective dosage amount of a pharmaceutical composition comprising an effective amount of a form of hyaluronic acid selected from hyaluronic acid and/or a pharmaceutically acceptable salt thereof associated with/bound with an effective amount of anti-sense to the gene, cDNA or RNA-DNA oligonucleotide or RNA-DNA oligonucleotide hybrids or messenger RNA implicated in the disease or condition in a suitable pharmaceutically acceptable diluent.

The embodiments of the invention in which an exclusive property or privilege is claimed are as follows:  
     
         1 . A sterile pharmaceutical composition comprising a gene therapy agent associated with/bound to hyaluronic acid or a pharmaceutically acceptable salt thereof, together with a pharmaceutically-acceptable excipient.  
     
     
         2 . The composition of  claim 1  wherein the form of hyaluronic acid has a molecular weight of less than 750,000 daltons.  
     
     
         3 . The composition of  claim 1  or  2  wherein the amount of the form of hyaluronan exceeds about 50 mg/kg person.  
     
     
         4 . The composition of  claim 1 ,  2  or  3  wherein the composition is a dosage form to be administered to a patient and the amount of the form of hyaluronan exceeds about 500 mg/70 kg person.  
     
     
         5 . The composition of any previous claim wherein the gene therapy agent is a DNA-RNA agent associated with/bound to the form of hyaluronic acid.  
     
     
         6 . The composition of any previous claim wherein the excipient comprises water and the gene therapy is a DNA-RNA agent.  
     
     
         7 . The composition according to any previous claim in which the gene therapy agent is a nucleotide sequence which is in the anti-sense orientation to a target sequence.  
     
     
         8 . The composition according to any previous claim in which the target nucleic acid sequence is a genomic DNA, a cDNA, a messenger RNA or an oligonucleotide or oligonucleotide hybrid.  
     
     
         9 . The composition according to  claim 1 ,  2 ,  3 ,  4 ,  5  or  6  in which the gene therapy agent comprises a nucleic acid sequence to be transferred into a target cell.  
     
     
         10 . The composition according to  claim 9  in which the nucleic acid sequence to be transferred is a genomic DNA, a cDNA, a messenger RNA or an oligonucleotide or an oligonucleotide of DNA protected at both ends by RNA.  
     
     
         11 . The composition according to  claim 10 , wherein the nucleic acid sequence comprises a sense sequence to be provided to a target cell in order to exert a function.  
     
     
         12 . The composition according to  claim 11 , in which the nucleic acid sequence comprises an anti-sense sequence to be provided to a target cell in order to inhibit the functioning of a nucleic acid present in the target cell.  
     
     
         13 . A dosage amount of a sterile composition of  claims 1  to  12  wherein the amount of the form of hyaluronic acid present exceeds at least about 50 mg.  
     
     
         14 . A method of treatment of a pathological condition which involves cells which express hyaluronic acid receptors in a subject in need of such treatment, comprising the step of administering an effective dose of a composition according to any one of  claims 1  to  13  to said subject.  
     
     
         15 . The method according to  claim 14 , in which the composition is administered systemically by injection.  
     
     
         16 . The method according to  claim 14 , in which the composition is administered topically.  
     
     
         17 . The method according to  claim 14 , in which the composition is administered directly into the tissue to be treated.  
     
     
         18 . The method according to  claim 14  or  15  in which the composition is administered intravenously.  
     
     
         19 . The method according to  claim 14  or  15  in which the composition is administered systemically.  
     
     
         20 . The method of preparing a composition according to any one of  claims 1  to  13 , comprising the step of associating or binding a gene therapy agent with hyaluronic acid or a pharmaceutically acceptable salt thereof, and isolating the thus-formed complex and combining with a pharmaceutical excipient to produce a pharmaceutical composition.  
     
     
         21 . The composition of any previous composition claim wherein the form of hyaluronic acid has a molecular weight less than about 750,000 daltons but greater than about 150,000 daltons.  
     
     
         22 . The method of any previous method claim wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons but greater than about 150,000 daltons.  
     
     
         23 . The composition of any previous composition claim wherein the form of hyaluronic acid is sodium hyaluronate.  
     
     
         24 . The method of any previous method claim wherein the form of hyaluronic acid is sodium hyaluronate.  
     
     
         25 . The method treating a human suffering a disease or condition caused by a gene, cDNA or RNA-DNA oligonucleotide or RNA-DNA oligonucleotide hybrids or messenger RNA implicated in a disease or condition involving cells that express hyaluronic acid receptors, the method comprising administering to such human, an effective dosage amount of a pharmaceutical composition comprising an effective amount of a form of hyaluronic acid selected from hyaluronic acid and/or a pharmaceutically acceptable salt thereof associated with/bound with an effective amount of anti-sense to the gene, cDNA or RNA-DNA oligonucleotide or RNA-DNA oligonucleotide hybrids or messenger RNA implicated in the disease or condition in a suitable pharmaceutically acceptable diluent.  
     
     
         26 . The method of  claim 25  wherein the pharmaceutical composition is sterile.  
     
     
         27 . The method of  claim 25  or  26  wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons.  
     
     
         28 . The method of  claim 25 ,  26  or  27  wherein the form of hyaluronic acid has a molecular weight greater than about 150,000 daltons.  
     
     
         29 . The method of  claim 25 ,  26 ,  27  or  28  wherein the form of hyaluronic acid is sodium hyaluronate and exceeds about 50 mg/70 kg person.  
     
     
         30 . The method of  claim 25 ,  26 ,  27 ,  28  or  29  wherein the amount of the form of hyaluronic acid in the pharmaceutical composition is at least about 500 mg/70 kg person.  
     
     
         31 . The method of  claim 25 ,  26 ,  27 ,  28 ,  29  or  30  wherein the effective amount of the pharmaceutical composition is administered intravenously.  
     
     
         32 . A pharmaceutical composition comprising a form of hyaluronic acid selected from hyaluronic acid and/or a pharmaceutically acceptable salt thereof and anti-sense to a gene implicated in a disease or condition together with a suitable diluent.  
     
     
         33 . The composition of  claim 32  wherein the pharmaceutical composition is a sterile composition and is in dosage form comprising an effective amount of the composition to treat a disease or condition.  
     
     
         34 . The composition of  claim 32  or  33  wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons.  
     
     
         35 . The composition of  claim 32 ,  33  or  34  wherein the form of hyaluronic acid has a molecular weight greater than about 150,000 daltons.  
     
     
         36 . The composition of  claim 32 ,  33 ,  34  or  35  wherein the form of hyaluronic acid is sodium hyaluronate and exceeds about 50 mg.  
     
     
         37 . The composition of  claim 32 ,  33 ,  34 ,  35  or  36  wherein the amount of the form of hyaluronic acid in the pharmaceutical composition is at least about 500 mg/70 kg person.  
     
     
         38 . A pharmaceutical composition comprising a form of hyaluronan selected from hyaluronan and/or a pharmaceutically acceptable salt thereof, associated with/bound to an RNA-DNA oligonucleotide which comprises a DNA residues flanked by RNA residues and wherein the DNA residue contains a mutant gene for a gene implicated in a disease or condition which involves cells expressing hyaluronic acid receptors, together with a suitable diluent.  
     
     
         39 . The composition of  claim 38  wherein the pharmaceutical composition is a sterile composition.  
     
     
         40 . The composition of  claim 38  or  39  wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons.  
     
     
         41 . The composition of  claim 38 ,  39  or  40  wherein the form of hyaluronic acid has a molecular weight greater than about 150,000 daltons.  
     
     
         42 . The composition of  claim 38 ,  39 ,  40  or  41  wherein the form of hyaluronic acid is sodium hyaluronate.  
     
     
         43 . The composition of  claim 38 ,  39 ,  40  or  41  the amount of the form of hyaluronic acid in the pharmaceutical composition is at least about 500 mg/70 kg person.  
     
     
         44 . A pharmaceutical composition comprising a form of hyaluronan associated with/bound to anti-sense nucleic acid, together with a pharmaceutically acceptable diluent.  
     
     
         45 . The composition of  claim 44  wherein the pharmaceutical composition is a sterile composition.  
     
     
         46 . The composition of  claim 44  or  45  wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons.  
     
     
         47 . The composition of  claim 44 ,  45  or  46  wherein the form of hyaluronic acid has a molecular weight greater than about 150,000 daltons.  
     
     
         48 . The composition of  claim 44 ,  45 ,  46  or  47  wherein the form of hyaluronic acid is sodium hyaluronate.  
     
     
         49 . The composition of  claim 44 ,  45 ,  46 ,  47  or  48  wherein the amount of the form of hyaluronic acid in the pharmaceutical composition is at least about 500 mg/70 kg person.  
     
     
         50 . A method of treating a human suffering from a disease or condition treatable by gene therapy and which disease or condition involves cells which express hyaluronic acid receptors, comprising administering an effective dosage amount of a composition of  claim 32  to  49  to a human.  
     
     
         51 . The use of a form of hyaluronan (such as hyaluronic acid and pharmaceutically acceptable salts thereof) and anti-sense nucleic acid in the manufacture of a pharmaceutical composition comprising a combination of the form of hyaluronan and anti-sense nucleic acid such as an anti-sense nucleic acid-hyaluronic acid complex together with a suitable diluent for the treatment of a human suffering a disease or condition treatable using gene therapy and which disease or condition involves cells which express hyaluronic acid receptors.  
     
     
         52 . The use of  claim 51  wherein the pharmaceutical composition is a sterile composition.  
     
     
         53 . The use of  claim 51  or  52  wherein the form of hyaluronic acid has a molecular weight less than 750,000 daltons.  
     
     
         54 . The use of  claim 51 ,  52  or  53  wherein the form of hyaluronic acid has a molecular weight greater than about 150,000 daltons.  
     
     
         55 . The use of  claim 51 ,  52 ,  53  or  54  wherein the form of hyaluronic acid is sodium hyaluronate.  
     
     
         56 . The use of  claim 51 ,  52 ,  53 ,  54  or  55  wherein the amount of the form of hyaluronic acid in the pharmaceutical composition is at least about 500 mg/70 kg person.  
     
     
         57 . The composition of any previous composition claim wherein the amount of the form of gene therapy is an effective amount of the form of gene therapy agent which is less than the usual or accepted amount understood to be used alone by persons skilled in the art to be used in the treatment.  
     
     
         58 . The dosage of any previous dosage claim wherein the amount of the form of gene therapy is an effective amount of the form of gene therapy agent which is less than the usual or accepted amount understood to be used by persons skilled in the art to be used alone in the treatment.  
     
     
         59 . The method of any previous method claim wherein the amount of the form of gene therapy is an effective amount of the form of gene therapy agent which is less than the usual or accepted amount understood to be used by persons skilled in the art to be used alone in the treatment.  
     
     
         60 . The use of any previous use claim wherein the amount of the form of gene therapy is an effective amount of the form of gene therapy agent which is less than the usual or accepted amount understood to be used by persons skilled in the art to be used alone in the treatment.