Georgia Health Sciences University Research Institute, Inc.

Augusta University Research Institute, Inc.

Medical College of Georgia Research Institute, Inc.

Sigma-tau Pharmaceuticals, Inc.

Vadivel Ganapathy

Puttur D Prasad

Muthusamy Thangaraju

A Lee Carter

Pamela M Martin

Gail Cresci

Frederick H Leibach

Robert G Martindale

Gianfranco Fornasini

David F Lapp

Methods of using one or more fumaric acid esters or pharmacologically active salts, derivatives, analogues, or prodrugs thereof to increase expression of fetal hemoglobin (HbF) are disclosed. The methods typically include administering to a subject an effective amount of one or more fumaric acid esters optionally in combination or alternation with hydroxyurea to induce HbF expression in the subject in an effective amount to reduce one or more symptoms of a sickle cell disorder, a hemoglobinopathy, or a beta-thalassemia, or to compensate for a genetic mutation is the human beta-globin gene (HBB) or an expression control sequence thereof. Pharmaceutical dosage units and dosage regimes for use in the disclosed methods are also provided.

Methods of treating sickle cell disease and related disorders using fumaric acid esters

Prodrugs made up of biologically-active short-chain fatty acids or derivatives thereof conjugated to neutral or cationic amino acids capable of intracellular transport by ATB,are provided. The short-chain fatty acid or derivative thereof can be attached to the amino acid through a hydroxyl group of the amino acid to form a fatty acid ester of the amino acid, or it can be attached through the amino group of the amino acid to form a fatty-acid amide of the amino acid. Serine butyrate (O-butyryl serine) is a preferred prodrug. These prodrugs are useful for treatment of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. Methods of delivering biologically-active short-chain fatty acids or derivatives thereof to cells in need of these molecules and methods of treating diseases using the prodrugs of this invention are also provided.

Prodrugs of short-chain fatty acids and treatment methods

The present invention includes inhibitors of the amino acid transporter ATBand methods of uses thereof.

Inhibitors of the ATB(0,+) transporter and uses thereof

Pharmaceutical compositions containing an effective amount of a ligand for GPR109 to decrease intracellular cAMP levels of a subject in combination with an effective amount of a DNA methyl transferase inhibito to reduce or inhibit downregulation of GPR109 in the intestinal epithelial cells of the subject relative to a control are provided. It has been discovered that ligands for GPR109 can be used to treat one or more symptoms of cancer, inflammatory disorders, and diarrhea. Representative CPR109 ligands include, but are not limited to butyrate, &#x3b2;-hydroxybutyrate, nicotinic acid, acifran, and octanoate. Suitable DNA methyl transferase inhibitors include 5-azacytidine, 5-aza-2'-deoxytidine, 1-&#x3b2;-D-arabinfarnosyl-5-azacytosine and dihydro-5-azacytidine. Typically, the compositions are formulated to achieve a GPR109 ligand serum blood level of about 1 to about 1000 &#x3bc;M. The compositions are useful for the treatment of one or more symptoms of cancer. Preferred cancers that can be treated using the disclosed compositions include, but are not limited to colon cancer, breast cancer and leukemia. Methods for treating cancer, inflammatory disorders, and diarrhea are also provided.

Compositions comprising a GPR109 ligand for treating disorders of the digestive tract and/or cancer

A carnitine-containing peptide sequence, which is a substrate for a mammalian peptide transport system, which contains at least one carnitine residue with at least one amino acid residue bonded thereto via an amide or ester linkage.

Growing community of inventors

Martinez, GA, United States of America

Vadivel Ganapathy