Gene therapy for AADC deficiency
The present invention is directed to compositions and methods for treating aromatic L -amino acid decarboxylase (AADC) deficiency. This invention includes a method of treating AADC deficiency in a pediatric subject, comprising the steps of: (a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector, (b) stereotactically delivering the pharmaceutical formulation to at least one target site in the brain of the subject in a dose of an amount at least about 1.8×10 11 vg; wherein delivering the pharmaceutical formulation to the brain is optionally by frameless stereotaxy, and optionally wherein the dose is an amount of at least about 2.4×10 11 vg and in some embodiments wherein the pharmaceutical formulation comprises a rAAV2-hAADC vector concentration of about 5.7×10 11 vg/mL. This invention is also directed to methods for treating aromatic L -amino acid decarboxylase (AADC) deficiency, wherein the method optionally further comprises the step of administering a therapeutically effective dose of dopamine-antagonist to the subject such as risperidone. This invention is also directed to methods for treating aromatic L -amino acid decarboxylase (AADC) deficiency, wherein the method optionally comprises providing a pharmaceutical formulation comprising an rAAV2-hAADC vector, and empty capsids.
1. A method of treating AADC deficiency in a pediatric subject, comprising the steps of: (a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising (i) a WT AAV2 capsid, and (ii) a recombinant DNA DOC gene insert comprising a nucleic acid sequence encoding hAADC; and (b) stereotactically delivering the pharmaceutical formulation to at least one target site in the brain of the subject in a dose of an amount at least about 2.4×10 11 vg; wherein delivering the pharmaceutical formulation to the brain is by frameless stereotaxy and the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
2. The method of claim 1 , wherein the pharmaceutical formulation comprises a rAAV2-hAADC vector concentration of about 5.7×10 11 vg/mL.
3. The method of claim 1 , wherein the pharmaceutical formulation is delivered at a rate of about 3 μL/min.
4. The method of claim 1 , wherein the pharmaceutical formulation is delivered to at least one target site in a brain at a dose volume of about 80 μL per target site.
5. The method of claim 1 , wherein the recombinant DNA DDC gene insert further comprises: (i) a first inverted terminal repeat (ITR), (ii) a cytomegalovirus (CMV) immediate early promoter (IEP), (iii) a human β-globin partial intron 2/exon 3, (iv) an SV40 poly A tail, and (v) a second ITR; wherein the first ITR and second ITR flank the CMV IEP promoter and the Poly A tail.
6. The method of claim 5 , wherein the nucleic acid sequence encoding hAADC is an unmodified DDC cDNA.
7. The method of claim 1 , wherein the pharmaceutical formulation is delivered to a putamen of the brain.
8. The method of claim 1 , wherein the pharmaceutical formulation is delivered bilaterally to each putamen.
9. The method of claim 8 , wherein said bilateral delivery is to points about 1 mm to about 10 mm apart.
10. A method of treating AADC deficiency in a pediatric subject, comprising the steps of: (a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising (i) a WT AAV2 capsid, and (ii) a recombinant DNA DDC gene insert comprising a nucleic acid sequence encoding hAADC; and (b) stereotactically delivering the pharmaceutical formulation to at least one target site in the brain of the subject in a dose of an amount at least about 2.4×10 11 vg, wherein the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
11. A method of treating AADC deficiency in a pediatric subject aged less than about 3 years, comprising the steps of: (a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising (i) a WT AAV2 capsid, and (ii) a recombinant DNA DDC gene insert comprising a nucleic acid sequence encoding hAADC; and (b) stereotactically delivering the pharmaceutical formulation to at least one target site in the brain of the subject in a dose of an amount at least about 2.4×10 11 vg, wherein the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
12. A method of treating AADC deficiency in a pediatric subject aged about 3 or more years, comprising the steps of: (a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising (i) a WT AAV2 capsid, and (ii) a recombinant DNA DDC gene insert comprising a nucleic acid sequence encoding hAADC; and (b) stereotactically delivering the pharmaceutical formulation to at least one target site in the brain of the subject in a dose of at least about 2.4×10 11 vg, wherein the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
13. The method of claim 1 , further comprising the step of: (c) administering a therapeutically effective dose of dopamine-antagonist to the subject.
14. The method of claim 13 , wherein the dopamine-antagonist is clozapine, haloperidol, olanzapine paliperidone, quetiapine risperidone, or ziprasidone.
15. The method of claim 13 wherein the dopamine-antagonist is administered at a dose from about 0.1 mg daily to about 1000 mg daily.
16. A method of treating AADC deficiency in a pediatric subject, comprising the steps of: (a) providing a pharmaceutical formulation comprising an AAV2-hAADC vector comprising (i) a WT AAV2 capsid, and (ii) a recombinant DNA DDC gene insert comprising a nucleic acid sequence encoding hAADC; and (b) delivering the pharmaceutical formulation to the brain of the subject in a dose of an amount at least about 2.4×10 11 vg, and (c) administering a therapeutically effective dopamine-antagonist to the subject, wherein the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
17. The method of claim 16 , wherein the dopamine-antagonist is administered from about the beginning of week-4 after gene-transduction until at least about the end of 12-weeks after gene-transduction.
18. The method of claim 16 , wherein the dopamine-antagonist is clozapine, olanzapine paliperidone, quetiapine, risperidone, or ziprasidone.
19. The method of claim 16 , wherein the dopamine-antagonist is administered at a dose from about 0.1 mg daily to about 1000 mg daily.
20. A pharmaceutical formulation comprising: (a) an rAAV2 hAADC vector at a concentration of about 5.7×10 11 vg/mL or about 7.5×10 11 vg/mL, wherein the rAAV2 hAADC vector comprises (i) a WT AAV2 capsid, and (ii) a recombinant DNA DDC gene insert comprising a nucleic acid sequence encoding hAADC; (b) 1×PBS; (c) about 200 mM NaCl; and (d) empty AAV2 capsids at a percentage from at least about 50% cp/cp up to about 90% cp/cp.
21. The method of claim 10 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.
22. The method of claim 1 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.
23. The method of claim 10 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.
24. The method of claim: 11 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.
25. The method of claim 12 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.
26. The method of claim 16 , wherein the percentage of empty AAV2 capsids is at least about 75% cp/cp.