Long lasting drug formulations

• US 8,877,175 B2
• Filed: 02/26/2013
• Issued: 11/04/2014
• Est. Priority Date: 09/14/2006
• Status: Expired due to Fees

• Current Assignee: Medgenics Medical Israel Ltd.
• Original Assignee: Medgenics Medical Israel Ltd.
• Inventors: Stern, Baruch S., Pearlman, Andrew
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): Montanari, David A
• Application Number:
  US13/776,745
• Publication Number:
  US 20130251679A1
• Time in Patent Office: 616 Days
• Field of Search: 424/93.1
• US Class Current: 424/93.1
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 35/36 Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells islets of Langerhans A61K35/39
• 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 48/0066 Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 48/0091 Purification or manufacturing processes for gene therapy compositions
• CPC Class Codes: A61P 7/06 Antianaemics
• 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 erythropoietin 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 erythropoietin.

Claims

1. A method of treating anemia in a human subject in need over a sustained time period comprising the steps of:

(a) providing at least one autologous erythropoietin secreting genetically modified dermal micro-organ that comprises a helper-dependent adenovirus vector comprising the nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences, wherein said nucleic acid comprises SEQ ID NO;

11,

(b) determining the erythropoietin secretion levels of the at least one genetically modified dermal micro-organ in step (a) in vitro,

(c) implanting the autologous genetically modified dermal micro-organ of step (b) in said human subject at an effective dosage at a site selected from the group consisting of subcutaneously, subdermally and intradermally,

(d) measuring hemoglobin levels in the blood of said human subject from step (c); and

(e) maintaining hemoglobin levels in said human subject at 9-11 g/dl in at least 50% of the measurements for at least one month, thereby treating anemia in a human subject.

2. The method of claim 1, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 18-150 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

3. The method of claim 2, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 18-30 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

4. The method of claim 2, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 30-50 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

5. The method of claim 2, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 50-65 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

6. The method of claim 2, wherein said effective dosage is determined based on:

a. said subject′

s weight;

b. said subject′

s historical hemoglobin levels; and

c. the average amount of erythropoientin administered to said subject in the one month prior said implanting step.

7. The method of claim 1, wherein said measured hemoglobin levels are 9-11 g/dl in at least 50% of the measurements for at least six months.

8. The method of claim 1, further comprising a step of implanting at a later date to said human subject, at least one additional autologous erythropoietin secreting genetically modified dermal micro-organ that comprises a helper-dependent adenovirus vector comprising the nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences, wherein said nucleic acid comprises SEQ ID NO:

11.

9. The method of claim 1, further comprising a step of maintaining said at least one genetically modified dermal micro-organ in vitro for at least 9 days, prior to said implantation step.

10. The method of claim 1, wherein said subject is selected from a group consisting of:

a. a subject suffering from;

renal failure, chronic renal failure, chemotherapy induced anemia, anemia as a result of HIV treatments, microangiopathic haemolytic anemia, anemia as a result of prematurity, an inflammatory condition including rheumatoid arthritis, an infection, anemia associated with cancers including multiple myeloma and non-Hodgkin lymphoma, hematopoietic stem cell disorders, sickle cell anemia or thalassemia; and

b. a subject in need of accelerated erythroid repopulation after bone marrow transplantation;

or any combination thereof.

11. The method of claim 10, wherein said subject suffering from chronic renal failure is suffering from chronic kidney disease (CKD) or end stage renal disease (ESRD).

12. A method of increasing or maintaining physiological hemoglobin levels in a human subject in need over a sustained time period comprising the steps of:

(a) providing at least one autologous erythropoietin secreting genetically modified dermal micro-organ that comprises a helper-dependent adenovirus vector comprising the nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences, wherein said nucleic acid comprises SEQ ID NO;

11,

(b) determining the erythropoietin secretion levels of the at least one genetically modified dermal micro-organ in step (a) in vitro,

(c) implanting the autologous genetically modified dermal micro-organ of step (b) in said human subject at an effective dosage at a site selected from the group consisting of subcutaneously, subdermally and intradermally,

(d) measuring hemoglobin levels in the blood of said human subject from step (c); and

(e) maintaining hemoglobin levels in said human subject at 9-11 g/dl in at least 50% of the measurements for at least one month, thereby increasing or maintaining physiological hemoglobin levels in a human subject.

13. The method of claim 12, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 18-150 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

14. The method of claim 13, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 18-30 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

15. The method of claim 13, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 30-50 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.

16. The method of claim 13, wherein the autologous genetically modified dermal micro-organ to be implanted provides said an effective dosage of 50-65 U erythropoietin/Kg body weight of said subject/day, as determined by in vitro secretion of erythropoietin from the genetically modified micro-organ.