Non-ionic, low osmolar contrast agents for delivery of antisense oligonucleotides and treatment of disease

Abstract

Disclosed are compositions comprising an antisense oligonucleotide and a non-ionic, low-osmolar contrast agent. Also disclosed are methods of delivering an antisense oligonucleotide to a target site comprising incorporating the antisense oligonucleotide into a composition comprising a non-ionic, low-osmolar contrast agent. Also disclosed are methods of treating a neurodegenerative disease comprising administering one or more of the compositions disclosed herein.

1 - 9 . (canceled) 
     
     
         10 . A method of delivering an antisense oligonucleotide to a tissue, organ, or system in a subject comprising administering to the subject a composition comprising an antisense oligonucleotide and a non-ionic, low-osmolar contrast agent. 
     
     
         11 . The method of  claim 10 , wherein the tissue, organ, or system comprises the central nervous system, peripheral nervous system, autonomic nervous system, brain, spinal cord, cardiac muscle, skeletal muscle, liver, pancreas, prostate, eyes, kidneys, small intestines, large intestines, stomach, spleen, thymus, pituitary gland, thyroid gland, bone marrow, bone, cartilage, or cancerous tissue. 
     
     
         12 . A method of treating a neurological disease in a patient in need thereof comprising administering to the patient a composition comprising an antisense oligonucleotide and a non-ionic, low-osmolar contrast agent. 
     
     
         13 . The method of  claim 12 , wherein the neurological disease is selected from the group consisting of Alzheimer's disease, Spinal muscular atrophy (SMA), Myotonic dystrophy, Huntington's disease, Parkinson's disease, Spinocerebellar degeneration, Spinocerebellar ataxia, Friedreich's ataxia, Ataxia telangiectasia, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Vasomotor ataxia, Vestibulocerebellar, Ataxiadynamia, Ataxiophemia, Amyotrophic lateral sclerosis, and Olivopontocerebellar atrophy. 
     
     
         14 . A method of delivering an antisense oligonucleotide to a tissue in a subject comprising administering to the subject a composition comprising an antisense oligonucleotide and a non-ionic, low-osmolar contrast agent to the subject. 
     
     
         15 . The method of  claim 14 , wherein the antisense oligonucleotide is delivered to the central nervous system, peripheral nervous system, autonomic nervous system, brain, spinal cord, cardiac muscle, skeletal muscle, liver, pancreas, prostate, eyes, kidneys, small intestines, large intestines, stomach, spleen, thymus, pituitary gland, thyroid gland, bone marrow, bone, cartilage, or cancerous tissue. 
     
     
         16 . The method of  claim 15  wherein the antisense oligonucleotide is delivered to the central nervous system of the subject. 
     
     
         17 . The method of  claim 16 , wherein the morpholino is delivered to the brain. 
     
     
         18 . The method of  claim 16 , wherein the morpholino is delivered to the spinal cord. 
     
     
         19 . The method of  claim 16 , wherein the morpholino is delivered to a glial cell. 
     
     
         20 . The method of  claim 19 , wherein the glial cell is an astrocyte. 
     
     
         21 . The method of  claim 14 , wherein the antisense oligonucleotide is a morpholino, siRNA, or shRNA. 
     
     
         22 . The method of  claim 21 , wherein the morpholino antisense oligonucleotide disrupts translation, binds to a target nucleotide, induces exon skipping, blocks an intron splice silencer, blocks an exon splice enhancer, binds to a repeat nucleotide sequence, or blocks binding to a sequence in toxic RNA. 
     
     
         23 . The method of  claim 21 , wherein the antisense oligonucleotide is a morpholino. 
     
     
         24 . The method of  claim 23 , wherein the morpholino is delivered to a lower motor neuron. 
     
     
         25 . The method of  claim 23 , wherein the morpholino binds to a SMN, a mutated SOD1 gene, C9orf72 repeats, alpha-synuclein, DMPK repeats, ZNF9 repeats, or a negative regulatory element in intron 6 or intron 7 of SMN2. 
     
     
         26 . The method of  claim 25 , wherein the morpholino that binds SMN2, binds SMN2 between nucleotides 67 and 112, upstream of exon 7 (E1) or SMN2 10 nucleotides downstream of exon 7 (intronic splicing silencer N1 (ISS-N1)). 
     
     
         27 . The method of  claim 26 , wherein the morpholino binds to a nucleic acid comprising SEQ ID NO: 1 or a fragment thereof at least 15 nucleotides long. 
     
     
         28 . The method of  claim 26 , wherein the morpholino comprises the sequence set forth in SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7. 
     
     
         29 . The method of  claim 14 , wherein the non-ionic, low-osmolar contrast agent is iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol or ioxilan. 
     
     
         30 - 48 . (canceled)