AAV-IDUA vector for treatment of MPS I-associated blindness
Inventors
HIRSCH, MATTHEW LOUIS • Samulski, Richard Jude
Assignees
University of North Carolina at Chapel Hill • Calcimedica Inc
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Publication Number
US-12201697-B2
Publication Date
2025-01-21
Expiration Date
Abstract
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.
Core Innovation
The invention relates to mucopolysaccharidosis I (MPS I) corneal disease and a gene-therapy strategy in which a codon-optimized human alpha-L-iduronidase (IDUA), referred to as opt-IDUA, is delivered to the cornea to express IDUA throughout the corneal stroma. The strategy uses a recombinant nucleic acid encoding human IDUA with a nucleotide sequence codon-optimized for expression in human cells, and includes an adeno-associated virus (AAV) vector genome and an AAV particle containing the codon-optimized IDUA sequence.
The disclosed approach further includes AAV variants employing AAV8/9 chimeric capsid (8G9) and AAV particles selected from AAV2, AAV8, and AAV9. A pharmaceutical composition is provided that includes the recombinant AAV particles for cornea-targeted delivery and treatment, prevention, and management of corneal clouding and blindness.
The background problem addressed is MPS I-associated corneal disease leading to corneal clouding and blindness, where delivery and expression of functional IDUA in the cornea is required. The disclosed approach is framed as delivering IDUA to the cornea to restore IDUA function, including restoring IDUA activity and expression in corneal tissues.
Claims Coverage
The provided claim structure includes inventive features centered on a codon-optimized human IDUA recombinant nucleic acid, an AAV vector genome and AAV particle containing that nucleic acid, and cornea delivery for MPS I-associated corneal clouding.
Codon-optimized human IDUA recombinant nucleic acid sequence
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.
AAV vector genome containing the IDUA nucleic acid
An adeno-associated virus (AAV) vector genome comprising the nucleic acid described in the independent claim.
AAV particle selected from AAV2, AAV8, and AAV9
An AAV particle, where the AAV particle is specifically an AAV2, AAV8, or AAV9 particle.
Cornea delivery of IDUA using an AAV particle
A method for delivering IDUA to a subject’s cornea by administering an effective amount of an AAV particle to the cornea, thereby delivering IDUA to the cornea.
Treatment of MPS I-associated corneal clouding by cornea administration
A method treats mucopolysaccharidosis I (MPS I)-associated corneal clouding by administering a therapeutically effective amount of the AAV particles to the cornea of a subject in need.
The claim coverage centers on a codon-optimized human IDUA recombinant nucleic acid with sequence identity to SEQ ID NO:1, packaged into an AAV vector genome and AAV particle, and used for cornea delivery to treat MPS I-associated corneal clouding.
Stated Advantages
Restored IDUA activity in MPS I patient fibroblasts.
Efficient corneal transduction and IDUA expression in human cornea explants.
Functional increase in IDUA activity.
No increased apoptosis.
Corneal cloudiness clearance in vivo in MPS1 canines.
Management of transient edema/immune effects.
Documented Applications
Cornea-targeted delivery and treatment, including prevention and management of MPS I-associated corneal clouding and blindness, using codon-optimized opt-IDUA delivered by recombinant AAV particles.
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