Aptamer-mRNA conjugates for targeted protein or peptide expression and methods for their use

• US 9,388,418 B2
• Filed: 11/14/2014
• Issued: 07/12/2016
• Est. Priority Date: 06/12/2011
• Status: Active Grant

• Current Assignee: City of Hope
• Original Assignee: City of Hope
• Inventors: Rossi, John J., Bobbin, Maggie
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US14/541,639
• Publication Number:
  US 20150166998A1
• Time in Patent Office: 606 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/12 Macromolecular compounds
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/1132 against retroviridae, e.g. HIV
• CPC Class Codes: C12N 15/115 Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/16 Aptamers
• CPC Class Codes: C12N 2310/3519 Fusion with another nucleic acid
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12Y 301/21004 : Type II site-specific deoxyribonuclease (3.1.21.4)

Abstract

An aptamer-mRNA conjugate is provided. The aptamer-mRNA conjugate may include an aptamer component that binds a membrane associated protein on a target cell and an mRNA component that is expressed by the target cell.

Claims

1. A method for treating a disease, comprising administering a therapeutically effective dose of a pharmaceutical composition to a subject suffering from a disease, the pharmaceutical composition comprises one or more aptamer-mRNA conjugates, wherein each aptamer-mRNA conjugate comprises:

an aptamer component that binds a membrane associated protein on a target cell; and

an mRNA component that is expressed by the target cell,

wherein the mRNA component is an mRNA molecule.

2. The method of claim 1, wherein the disease is a cancer.

3. The method of claim 2, wherein the cancer is bone cancer, bladder cancer, brain cancer, breast cancer, cancer of the urinary tract, carcinoma, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, lung cancer, lymphoma (B cell and T cell) and leukemia, melanoma, ovarian cancer, pancreatic cancer, pituitary cancer, prostate cancer, rectal cancer, renal cancer, sarcoma, testicular cancer, thyroid cancer, or uterine cancer.

4. The method of claim 1, wherein the disease is a chronic viral infection.

5. The method of claim 4, wherein the chronic viral infection is hepatitis, papillomavirus, herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Smallpox virus, and human or simian immunodeficiency virus (HIV/SHIV).

6. The method of claim 1, wherein the disease is a genetic disorder.

7. The method of claim 6, wherein the genetic disorder is muscular dystrophy, hemophilia, Huntington'"'"'s disease, alpha-1 antitrypsin deficiency, Alzheimer'"'"'s disease, various forms of breast cancer (e.g., BRCA1), cystic fibrosis, galactosemia, congenital hyperthyroidism, maple syrup urine disease, neurofibromatosis I, phenylketonuria, sickle cell disease, and Smith-Lemli-Opitz (SLO-RSH) syndrome, familial hypercholesterolemia, polycystic kidney disease, hereditary spherocytosis, Marfan syndrome, Tay-Sachs disease, mucoplysacchariddoses, and glycogen storage diseases.

8. The method of claim 1, wherein the membrane associated protein is CD4, CD19, DC-SIGN/CD209, HIV envelope glycoprotein gp120, CCR5, EGFR/ErbB1, EGFR2/ErbB2/HER2, EGFR3/ErbB3, EGFR4/ErbB4, EGFRvIII, Transferrin Receptor, PSMA, VEGF, VEGF-2, CD25, CD11a, CD33, CD20, CD3, CD52, CEA, TAG-72, LDL receptor, insulin receptor, megalin receptor, LRP, mannose receptor, P63/CKAP4 receptor, arrestin, ASGP, CCK-B, HGFR, RON receptor, FGFR, ILR, AFP, CA125/MUC16, PDGFR, stem cell factor receptor, colony stimulating factor-1 receptor, integrins, TLR, BCR or BAFF-R.

9. The method of claim 1, wherein the mRNA component is a therapeutic agent.

10. The method of claim 9, wherein the therapeutic agent is a cytotoxin, an enzyme, or an antibody or functional fragment thereof.

11. The method of claim 1, wherein the mRNA component is a fluorescent or bioluminescent protein.