Naturally-Occurring CpG Oligonucleotide Compositions and Therapeutic Applications Thereof

Abstract

The present invention relates to combination therapies for the treatment of a variety of disorders in mammals, including hepatic disorders and cancer. The combination of agents includes naturally-occurring (versus synthetic) oligonucleotides, particularly immunostimulatory oligodeoxynucleotides such as CpG ODNs, obtained from a natural source and one or more extracts from a Gram positive bacteria, such as Lactobacillus spp.

What is claimed is: 
     
         1 . A composition for delivery of a therapeutic agent across the mucosa of a subject for the treatment of a hepatic disorder, the composition comprising:
 (a) a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and   (b) a naturally-occurring immunostimulatory oligodeoxynucleotide (ODN);   wherein the cell wall lysate and the ODN are present in an amount effective to treat an immune disorder.   
     
     
         2 . The composition of  claim 1 , further comprising a control release agent, a promoter, a carrier, or a combination thereof. 
     
     
         3 . The composition of  claim 1 , wherein the gram positive bacteria is selected from the group consisting of  Bacillus coagulans  ( Lactobacillus sporogenes )  Streptococcus thermophilus, Bifidobacterium animalis  (especially  B. animalis , subspecies  animalis ),  Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii  subsp.  bulgaricus, Lactococcus lactis, Lactococcus lactis  subsp.  lactis  ( Streptococcus lactis ),  Streptococcus thermophilus, Bifidobacterium lactis, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus , and  Lactobacillus helveticus , and combinations thereof. 
     
     
         4 . The composition of  claim 2 , wherein the promoter is selected from the group consisting of amino acids, amino sugars, and sugars. 
     
     
         5 . The composition of  claim 1 , wherein the gram positive bacteria is  Lactobacillus delbrueckii.    
     
     
         6 . A composition for the treatment of complications of a hepatic disorder in a subject suffering from one or more hepatic disorders, the composition comprising a therapeutically effective amount of:
 a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and   at least one Toll Like receptor (TLR) 9 agonist,   the gram-positive bacteria being selected from the  Lactobacillus  family of bacteria.   
     
     
         7 . The composition of  claim 6 , wherein the TLR 9 agonist is a CpG oligodeoxynucleotide (CpG ODN). 
     
     
         8 . The composition of  claim 7 , wherein the CpG ODN is naturally-occurring within the bacterial lysate. 
     
     
         9 . The composition according to  claim 6 , wherein the hepatic disorder is characterized by overexpression of TLR 9 and one or more of TLR 2, TLR 4 and TLR 7. 
     
     
         10 . The composition of  claim 1 , wherein the composition is a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, and a dissolving tablet. 
     
     
         11 . The composition of  claim 10 , wherein the dissolving tablet is selected from the group consisting of a slow-dissolving tablet and a quick-dissolving tablet. 
     
     
         12 . The composition of  claim 1 , wherein the mucosa is selected from the group consisting of the oral mucosa, sublingual mucosa, the buccal mucosa, and a combination thereof. 
     
     
         13 . The composition of  claim 1 , further comprising a chemotherapeutic agent. 
     
     
         14 . The composition of  claim 1 , wherein the composition exhibits a modulation of at least one Toll Like receptors (TLRs) in a subject to whom the composition is administered. 
     
     
         15 . The composition of  claim 14 , wherein the TLR modulated is chosen from TLR 2, TLR 4, TLR 7 and TLR 9. 
     
     
         16 . A dietary supplement comprising the composition of  claim 1 . 
     
     
         17 . A method of inducing an immune response to a tumor in a subject, the method comprising:
 selecting a subject with a tumor; and   administering to the subject a therapeutically effective amount of a composition comprising:
 (a) a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and 
 (b) a naturally-occurring CpG oligodeoxynucleotide (ODN), 
   thereby inducing the immune response to the tumor in the subject.   
     
     
         18 . The method of  claim 17 , wherein the naturally-occurring CpG oligodeoxynucleotide is derived from a bacterial lysate. 
     
     
         19 . The method of  claim 17 , wherein the CpG ODN is selected from the group consisting of the C-type, D-type, or K-type CpG ODN. 
     
     
         20 . The method of  claim 17 , wherein the immune response comprises the production of antibodies.