AAV-IDUA vector for treatment of MPS I-associated blindness
This invention relates to viral vectors for delivery of alpha-L-iduronidase to the cornea of a subject and methods of using the same for treatment and prevention of corneal clouding and blindness in a subject due to mucopolysaccharidosis I.
1. A recombinant nucleic acid comprising a sequence encoding human alpha-L-iduronidase (IDUA), wherein the nucleotide sequence has been codon-optimized for expression in human cells, and wherein the recombinant nucleic acid comprises a nucleotide sequence at least 90% identical to SEQ ID NO:1.
2. The recombinant nucleic acid of claim 1 , comprising the nucleotide sequence of SEQ ID NO: 1.
3. An adeno-associated virus (AAV) vector genome comprising the nucleic acid of claim 1 .
4. The AAV vector genome of claim 3 , wherein the nucleic acid is operably linked to a constitutive promoter.
5. A cell in vitro comprising the AAV vector genome of claim 3 .
6. The cell of claim 5 , wherein the vector genome is stably incorporated into the cell genome.
7. An AAV particle comprising the AAV vector genome of claim 3 .
8. The AAV particle of claim 7 , wherein the AAV particle is an AAV2, AAV8, or AAV9 particle.
9. The AAV particle of claim 7 , wherein the AAV particle is a chimeric AAV8/AAV9 particle.
10. A pharmaceutical formulation comprising the AAV particle of claim 7 and a pharmaceutically acceptable carrier.
11. A method of delivering IDUA to the cornea of a subject, comprising administering to the cornea of the subject an effective amount of the AAV particle of claim 7 , thereby delivering IDUA to the cornea of the subject.
12. A method of treating mucopolysaccharidosis I (MPS I)-associated corneal clouding in a subject in need thereof, comprising administering to the cornea of the subject a therapeutically effective amount of the AAV particle of claim 7 , thereby treating MPS I-associated corneal clouding in the subject.
13. A method of delivering IDUA to a cornea in vitro or ex vivo, comprising contacting the cornea with an effective amount of the AAV particle of claim 7 , thereby delivering IDUA to the cornea.
14. The method of claim 13 , further comprising transplanting the cornea to a subject in need thereof.
15. The method of claim 11 , wherein the AAV particle is administered to the cornea by intrastromal injection.
16. The method of claim 11 , wherein the AAV particle is administered to the cornea topically.
17. The method of claim 11 , wherein the subject is a human subject.