Long lasting drug formulations

• US 20080090777A1
• Filed: 09/12/2007
• Published: 04/17/2008
• Est. Priority Date: 09/14/2006
• Status: Active Grant

• Current Assignee: Medgenics Medical Israel Ltd.
• Original Assignee: Medgenics Medical Israel Ltd.
• Inventors: Pearlman, Andrew
• Granted Patent: US 9,155,749 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 14/505 : Erythropoietin [EPO]
• CPC Class Codes: C12N 15/86 : Viral vectors
• CPC Class Codes: C12N 15/88 : using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 2710/10343 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention is directed to long-lasting therapeutic formulations and their methods of use wherein the formulation comprises a genetically modified micro-organ that comprises a vector which comprises a nucleic acid sequence operably linked to one or more regulatory sequences, wherein the nucleic acid sequence encodes a therapeutic polypeptide, such as erythropoietin or interferon alpha.

Claims

1. A long-lasting therapeutic formulation comprising a genetically modified micro-organ, said micro organ comprising a vector comprising a nucleic acid sequence operably linked to one or more regulatory sequences, wherein said nucleic acid sequence encodes a therapeutic polypeptide and whereby said formulation increases expression levels of said therapeutic polypeptide by more than 5% over basal levels and said increased levels persist for greater than one month.

2. The formulation of claim 1, wherein said regulatory sequence comprises a CAG promoter.

3. The formulation of claim 1, wherein said regulatory sequence comprises a CMV promoter.

4. The formulation of claim 1, wherein said regulatory sequence comprises a SV40 polyadenylation sequence.

6. The formulation of claim 1, wherein said vector is derived from adenovirus.

7. The formulation of claim 6, wherein said adenovirus is a helper-dependent adenovirus.

8. The formulation of claim 1, wherein said vector is derived from adeno-associated virus (AAV) vector.

10. The formulation of claim 1, wherein said vector is a mini-circle DNA plasmid.

11. The formulation of claim 1, herein said nucleic acid sequence encoding said therapeutic polypeptide is optimized for increased expression levels, duration, or a combination thereof, of said therapeutic polypeptide.

12. The formulation of claim 1, wherein said genetically modified micro-organ is a genetically modified dermal micro-organ.

13. The formulation of claim 1, wherein said therapeutic polypeptide is erythropoietin.

14. The formulation of claim 1, wherein said therapeutic polypeptide is interferon alpha.

15. The formulation of claim 14, wherein said interferon alpha is interferon alpha 2b.

106. The formulation of claim 13, wherein said optimized nucleic acid sequence is greater than 85% homologous to SEQ ID No:

1.

107. The formulation of claim 15, wherein said optimized nucleic acid sequence is greater than 85% homologous to SEQ ID No:

2.

5. (canceled)

9. (canceled)

16. A method of providing a therapeutic polypeptide to a subject in need over a sustained period comprising:

a. providing a formulation comprising one or more genetically modified micro-organs, said micro-organs comprising a vector comprising a nucleic acid sequence operably linked to one or more regulatory sequences; and

b. implanting said genetically modified micro-organ in said subject, wherein said nucleic acid sequence encodes said therapeutic polypeptide and whereby said therapeutic polypeptide levels are increased by more than 5% over basal levels and said increased therapeutic polypeptide expression levels are maintained for greater than one month.

17. The method of claim 16, further comprising the step of determining said therapeutic polypeptide expression levels in vitro prior to step (b).

18. The method of claim 16, further comprising the step of determining said therapeutic polypeptide expression levels in vivo.

19. The method of claim 16, wherein said regulatory sequence comprises a CAG promoter.

20. The method of claim 16, wherein said regulatory sequence comprises a CMV promoter.

21. The method of claim 16, wherein said regulatory sequence comprises a SV40 polyadenylation sequence.

22. The method of claim 16, wherein said vector is virally-derived.

23. The method of claim 22, wherein said virally-derived vector is derived from adenovirus.

24. The method of claim 23, wherein said adenovirus is a helper-dependent adenovirus.

25. The method of claim 22, wherein said vitally-derived vector is derived from adeno-associated virus (AAV) vector.

26. The method of claim 16, wherein said vector is a plasmid.

27. The method of claim 16, wherein said vector is a mini-circle DNA plasmid.

28. The method of claim 16, wherein said nucleic acid sequence encoding said therapeutic polypeptide is optimized for increased expression levels, duration, or a combination thereof, of said therapeutic polypeptide.

29. The method of claim 16, wherein said genetically modified micro-organ is a genetically modified dermal micro-organ.

30. The method of claim 16, herein said therapeutic polypeptide is erythropoietin.

31. The method of claim 16, wherein said therapeutic polypeptide is interferon alpha.

32. The method of claim 31, wherein said interferon alpha is interferon alpha 2b.

33-99. -99. (canceled)

100. A nucleic acid sequence with greater than 85% homology to SEQ ID No:

1.

101. A vector comprising the nucleic acid sequence of claim 100.

102. A cell comprising the vector of claim 101.

103. A nucleic acid sequence with greater than 85% homology to SEQ ID No:

2.

104. A vector comprising the nucleic acid sequence of claim 103.

105. A cell comprising the vector of claim 104.