Claims for Patent: 9,593,312

Summary for Patent: 9,593,312

Title:	Viral vector construct for neuron specific optimized continuous DOPA synthesis in vivo
Abstract:	The present invention relates to a one-vector expression system comprising a sequence encoding two polypeptides, such as tyrosine hydroxylase (TH) and GTP-cyclohydrolase 1 (GCH1). The two polypeptides can be should preferentially be expressed at a ratio between 3:1 and 15:1, such as between 3:1 and 7:1. The invention is useful in the treatment of catecholamine deficient disorders, such as dopamine deficient disorders including but not limited to Parkinson\'s Disease. Moreover, the present invention provides a method to deliver the vector construct in order to limit the increased production of the catecholamine to the cells in need thereof.
Inventor(s):	Bjorklund; Tomas (Lund, SE), Bjorklund; Anders (Lund, SE), Kirik; Deniz (Lund, SE)
Assignee:	Genepod Therapeutics AB (Lund, SE)
Application Number:	14/242,648
Patent Claims:	1. A method of treating a condition associated with catecholamine dysfunction, said method comprising administering to an individual in need of treatment a one-vector expression system wherein said vector is an adeno associated vector (AAV), said one-vector expression system comprising: i) a first expression cassette comprising a human Synapsin 1 promoter operably linked to a first nucleotide sequence encoding a GTP-cyclohydrolase 1 (GCH1) polypeptide, and ii) a second expression cassette comprising a second promoter operably linked to a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, wherein said second promotor is selected from the group consisting of a human Synapsin 1 promoter and a CMV promoter, and wherein the second expression cassette comprises an enhancer or regulator selected from the group consisting of an intron and a Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), such that, after said administering, the TH polypeptide is expressed at a higher level than said GCH1 polypeptide in one or more cells or tissues. 2. The method of claim 1, wherein said second promoter is a CMV promoter. 3. The method of claim 1, wherein said enhancer or regulator is an intron. 4. The method of claim 3, wherein said intron is preceded by said second promoter. 5. The method of claim 1, wherein after said administering, the TH polypeptide is expressed in one or more cells or tissues at a level at least three-fold greater than that of the GCH1 polypeptide, wherein said level is an enzyme activity level, protein level, mRNA level, or a level determined by the concentration of Tetrahydrobiopterin (BH.sub.4). 6. The method of claim 1, wherein one or both of said first expression cassette and said second expression cassette further comprises a polyadenylation sequence operably linked to said first nucleotide sequence or said second nucleotide sequence, respectively. 7. The method of claim 1, wherein the more 3' of said first and second expression cassettes comprises a 3' terminal repeat and the more 5' of said first and second expression cassettes comprises a 5' terminal repeat. 8. The method of claim 7, wherein said 5' and 3' terminal repeats are selected from Inverted Terminal Repeats and Long Terminal Repeats. 9. The method of claim 8, wherein said 5' and 3' terminal repeats are Inverted Terminal Repeats. 10. The method of claim 1, wherein the GCH1 polypeptide has an amino acid sequence at least 90% identical to SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. 11. The method of claim 1, wherein the GCH1 polypeptide has an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. 12. The method of claim 1, wherein the nucleotide sequence encoding the GCH1 polypeptide comprises SEQ ID NO:18. 13. The method of claim 1, wherein the TH polypeptide has an amino acid sequence at least 90% identical to SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13 or SEQ ID NO:14. 14. The method of claim 1, wherein the TH polypeptide has an amino acid sequence selected from SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO:12, SEQ ID NO:13 or SEQ ID NO:14. 15. The method of claim 1, wherein the nucleotide sequence encoding the TH polypeptide comprises SEQ ID NO:21. 16. The method of claim 1, wherein the AAV vector is a serotype 2 AAV vector. 17. The method of claim 16, wherein the serotype 2 AAV vector is packaged in a serotype 5 AAV capsid. 18. The method of claim 1, wherein the catecholamine dysfunction is catecholamine deficiency. 19. The method of claim 18, wherein the catecholamine deficiency is dopamine deficiency. 20. The method of claim 1, wherein said condition associated with catecholamine dysfunction is a disease or disorder of, or damage to, the central and/or peripheral nervous system. 21. The method of claim 1, wherein said condition associated with catecholamine dysfunction is a neurodegenerative disorder. 22. The method of claim 1, wherein said condition associated with catecholamine dysfunction is a disease of the basal ganglia. 23. The method of claim 1, wherein said condition associated with catecholamine dysfunction is a disease selected from the group consisting of Parkinson's Disease (PD), DOPA responsive dystonia, L-DOPA induced dyskinesia (LID), ADHD, schizophrenia, depression, vascular parkinsonism, essential tremor, chronic stress, genetic dopamine receptor abnormalities, chronic opioid, cocaine, alcohol or marijuana use, adrenal insufficiency, hypertension, noradrenaline deficiency, post-traumatic stress disorder, pathological gambling disorder, dementia, and Lewy body dementia. 24. The method of claim 23, wherein said condition associated with catecholamine dysfunction is Parkinson's Disease (PD).

Details for Patent 9,593,312

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2029-11-09
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2029-11-09
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2029-11-09