Gene therapy for AADC deficiency
Inventors
PYKETT, Mark • Thorn, Richard • Hwu, Wuh-Liang (“Paul”)
Assignees
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Publication Number
US-11865188-B2
Publication Date
2024-01-09
Expiration Date
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 1.8×1011 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 2.4×1011 vg and in some embodiments wherein the pharmaceutical formulation comprises a rAAV2-hAADC vector concentration of about 5.7×1011 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.
Core Innovation
The invention relates to a method of treating aromatic L-amino acid decarboxylase (AADC) deficiency in a pediatric subject by administering a pharmaceutical formulation that includes an rAAV2-hAADC vector. The vector includes a wild type AAV2 capsid and a recombinant DNA dopa decarboxylase (DDC) gene insert comprising a nucleic acid sequence encoding hAADC. The formulation is delivered to at least one target site in the brain.
The delivered dose is at least 1.8×10^11 vg, and the formulation further comprises empty AAV2 capsids at a percentage from about 50% cp/cp up to about 90% cp/cp. The method uses stereotaxy to deliver the pharmaceutical formulation to brain target sites, including the putamen, with bilateral delivery to each putamen.
The stereotaxy can be frameless stereotaxy. The invention further incorporates an empty capsid component in the pharmaceutical formulation, described as including empty AAV2 capsids and also decoy empty AAV2 capsids.
Claims Coverage
The independent claim covers one core treatment method with multiple refinements described by dependent claims: empty capsid fraction threshold, DDC gene insert element architecture, delivery approach, brain target site, and bilateral targeting and spacing.
R AAV2 hAADC formulation with wild type AAV2 capsid and recombinant DDC gene insert
Providing a pharmaceutical formulation comprising an rAAV2-hAADC vector comprising a wild type AAV2 capsid and a recombinant DNA dopa decarboxylase (DDC) gene insert comprising a nucleic acid sequence encoding hAADC.
Stereotaxic brain delivery at at least 1.8×10^11 vg dose
Delivering the pharmaceutical formulation to at least one target site in the brain of the pediatric subject in a dose of an amount of at least 1.8×10^11 vg, wherein the pharmaceutical formulation is delivered by stereotaxy.
Empty AAV2 capsids at 50% cp/cp to 90% cp/cp
Formulating the pharmaceutical formulation to further comprise empty AAV2 capsids at a percentage from about 50% cp/cp up to about 90% cp/cp.
DDC gene insert with defined 5′ to 3′ element order
In the recombinant DNA DDC gene insert, the elements are in 5′ to 3′ order including a first inverted terminal repeat (ITR), a cytomegalovirus (CMV) immediate early promoter (IEP), a human β-globin partial intron2/exon 3, a sequence encoding hAADC, and an SV40 poly A tail, and a second ITR.
Frameless stereotaxy delivery
Delivering the pharmaceutical formulation using frameless stereotaxy.
Putamen brain target site
Delivering the pharmaceutical formulation to the putamen of the brain.
Bilateral putamen delivery with target sites spaced about 1 mm to about 10 mm apart
Delivering the pharmaceutical formulation bilaterally to each putamen at target sites spaced about 1 mm to about 10 mm apart.
The inventive coverage focuses on pediatric AADC deficiency treatment using an rAAV2-hAADC formulation delivered stereotaxically to brain target sites at a dose of at least 1.8×10^11 vg, with an empty AAV2 capsid fraction from about 50% cp/cp to about 90% cp/cp, and refinements including specific DDC gene insert architecture, frameless stereotaxy, putamen targeting, and bilateral putamen targeting with spacing.
Stated Advantages
Higher and age-tailored dosing for pediatric treatment context.
Mitigation of gene-therapy induced dyskinesia.
Improved transduction.
Reduced immune interference.
Avoidance of skull-fixed frames by using frameless stereotaxy.
Documented Applications
Treating aromatic L-amino acid decarboxylase (AADC) deficiency in a pediatric subject using rAAV2-hAADC gene therapy delivered stereotaxically to brain target sites.
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