IP Library › Granted Patent US 12,409,235
Granted Patent B2
US 12,409,235 · App. 18/524,967 · Granted Sep 9, 2025

Gene therapy for AADC deficiency

Inventors: Mark Pykett (Cambridge, MA); Richard Thorn (Mendon, MA); Wuh-Liang (“Paul”) Hwu (Taipei, TW)
Assignee: National Taiwan University
A61K48/005A61K9/5184A61K31/4515A61K31/5513A61K48/00A61K48/0075A61K48/0083A61P25/00C12N9/88C12N15/113C12N15/625C12N15/8509C12N15/86C12N15/8645C12Y401/01028
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Quick Facts
Patent No.
US 12,409,235
App. No.
18/524,967
Granted
Sep 9, 2025
Kind
B2
Abstract

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.

Claims (24)

1. A method of treating aromatic L-amino acid decarboxylase (AADC) deficiency in a pediatric subject, the method comprising:

(a) providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising

(i) a wild type AAV2 capsid, and

(ii) a recombinant DNA dopa decarboxylase (DDC) gene insert comprising a nucleic acid sequence encoding hAADC; and

(b) delivering the pharmaceutical formulation of a dose amount of about 4.5×10 10 vg each to four target sites in the brain of the subject for a total dose amount of 1.8×10 11 vg; wherein the pharmaceutical formulation further comprises empty AAV2 capsids at a percentage from about 50% cp/cp up to about 90% cp/cp, wherein the pharmaceutical formulation is delivered by stereotaxy, wherein the pharmaceutical formulation is delivered at a rate of about 3 μL/min; and wherein the pharmaceutical formulation is delivered at a dose volume of about 80 μL per target site.

2. The method of claim 1 , wherein the percentage of empty AAV2 capsids is at least 75% cp/cp.

3. The method of claim 1 , wherein the pediatric subject is less than three years in age.

4. The method of claim 1 , wherein the pediatric subject is about three or more years in age.

5. The method of claim 1 , wherein the pediatric subject is human.

6. The method of claim 1 , wherein the nucleic acid sequence encoding hAADC is an unmodified DDC cDNA.

7. The method of claim 1 , wherein the recombinant DNA DDC gene insert comprises from 5′ to 3′ (i) a first inverted terminal repeat (ITR), (ii) a cytomegalovirus (CMV) immediate early promoter (IEP), (iii) a human β-globin partial intron2/exon 3, (iv) the nucleic acid sequence encoding hAADC, (v) a SV40 poly A tail, and (vi) a second ITR.

8. The method of claim 1 , wherein the pharmaceutical formulation comprises the rAAV2-hAADC vector at a concentration of about 5.7×10 11 vg/mL.

9. The method of claim 1 , wherein the pharmaceutical formulation is delivered by skull-fixed head frame stereotaxy.

10. The method of claim 1 , wherein the pharmaceutical formulation is delivered by frameless stereotaxy.

11. The method of claim 1 , wherein the pharmaceutical formulation is delivered to a putamen of the brain.

12. The method of claim 1 , wherein the pharmaceutical formulation is delivered bilaterally to each putamen.

13. The method of claim 1 , wherein the pharmaceutical formulation is delivered bilaterally to each putamen at target sites about 1 mm to about 10 mm apart.

14. The method of claim 1 , wherein the pharmaceutical formulation is delivered to two target sites separated dorsolaterally to each putamen.

15. The method of claim 1 , wherein the pharmaceutical formulation is delivered to a deep target site and a shallow target site separated dorsolaterally to each putamen.

16. The method of claim 15 , wherein the shallow target site is from about 10 mm to about 1 mm from the surface of the putamen and the deep target site is about 5 mm from the center of the putamen.

17. The method of claim 1 further comprising (c) administering a therapeutically effective dopamine-antagonist to the subject.

18. The method of claim 17 , 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.

19. The method of claim 17 , wherein the dopamine-antagonist is clozapine, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

20. The method of claim 17 , wherein the dopamine-antagonist is administered at a dose from about 0.1 mg daily to about 1000 mg daily.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 20, 2023
From: PYKETT, MARK; THORN, RICHARD
To: PTC THERAPEUTICS
Reel/Frame 065924/0693 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 20, 2023
From: PTC THERAPEUTICS
To: NATIONAL TAIWAN UNIVERSITY
Reel/Frame 065924/0811 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 20, 2023
From: HWU, WUH-LIANG
To: NATIONAL TAIWAN UNIVERSITY
Reel/Frame 066126/0079 →
Continuity (4)
Continuation 17157745 · Jan 25, 2021
Continuation 15951270 · Apr 12, 2018
Provisional Application 62485658 · Apr 14, 2017
Related Publication 20240100186A1 · Mar 28, 2024
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