Methods to treat mucopolysaccharide type I or deficiency in alpha-L-iduronidase using a recombinant adeno-associated virus encoding alpha-L-iduronidase
Inventors
McIvor, R. Scott • Belur, Lalitha R. • Low, Walter • Fairbanks, Carolyn • Kozarsky, Karen
Assignees
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Publication Number
US-9827295-B2
Publication Date
2017-11-28
Expiration Date
Abstract
A method to prevent, inhibit or treat one or more symptoms associated with a disease of the central nervous system by intrathecally, intracerebroventricularly or endovascularly administering a rAAV encoding a gene product associated with the disease, e.g., a mammal in which the gene product is absent or present at a reduced level relative to a mammal without the disease.
Core Innovation
The disclosed invention is directed to methods to inhibit or treat one or more symptoms of mucopolysaccharide type I (MPSI) in a mammal in need thereof by administering to a cisterna magna a composition comprising an rAAV9 or rAAVrh10 vector. The composition includes an open reading frame encoding alpha-L-iduronidase effective to inhibit or treat the one or more symptoms of MPSI.
A core aspect of the invention is the use of an rAAV vector delivering an open reading frame encoding alpha-L-iduronidase to the brain/CNS with the goal of restoring alpha-L-iduronidase enzyme activity. The disclosure states that AAV-9 can transduce adult brain/CNS and restore enzyme activity to wild-type or higher levels, with widespread restoration of IDUA activity and clearance/normalization of glycosaminoglycans (GAG) in brain regions.
The disclosure also emphasizes overcoming immune-related limitations by using immunomodulation in conjunction with the rAAV9 or rAAVrh10 alpha-L-iduronidase approach. It reports proof-of-principle in adult IDUA-deficient immunocompetent mice and further improvement with immunosuppression and/or immunotolerization.
Claims Coverage
The independent claims cover three main inventive themes, each centered on cisterna magna administration of an rAAV9 or rAAVrh10 vector carrying an open reading frame encoding alpha-L-iduronidase, with additional coverage for immune suppression or immunotolerization.
Cisterna magna delivery of rAAV9 or rAAVrh10 encoding alpha-L-iduronidase for MPSI symptom treatment
A method to inhibit or treat one or more symptoms of mucopolysaccharide type I (MPSI) in a mammal in need thereof, comprising administering to a cisterna magna of the mammal a composition comprising an amount of a recombinant adeno-associated virus (rAAV) 9 or rAAVrh10 vector comprising an open reading frame encoding alpha-L-iduronidase effective to inhibit or treat the one or more symptoms of MPSI.
Immune suppressant plus cisterna magna delivery of rAAV9 or rAAVrh10 encoding alpha-L-iduronidase
A method to inhibit or treat one or more symptoms of mucopolysaccharidosis type I (MPSI) in a mammal in need thereof, comprising administering to the mammal in need thereof an immune suppressant, and to a cisterna magna of the mammal a composition comprising an amount of a rAAV9 or rAAVrh10 vector comprising an open reading frame encoding alpha-L-iduronidase effective to inhibit or treat the one or more symptoms of MPSI.
Immunotolerized alpha-L-iduronidase deficient mammal treated by cisterna magna rAAV9 or rAAVrh10 encoding alpha-L-iduronidase
A method to inhibit or treat one or more symptoms associated with a deficiency in alpha-L-iduronidase (IDUA) in a mammal, comprising providing a mammal with a deficiency in alpha-L-iduronidase that is immunotolerized to alpha-L-iduronidase; and administering to a cisterna magna of the mammal a composition comprising an amount of a rAAV9 or rAAVrh10 vector comprising an open reading frame encoding alpha-L-iduronidase effective to inhibit or treat the one or more symptoms associated with the deficiency in alpha-L-iduronidase.
Across the independent claims, the coverage centers on cisterna magna administration of rAAV9 or rAAVrh10 vectors encoding alpha-L-iduronidase for treating MPSI/IDUA-related symptoms, with additional claim coverage for immune suppressant co-administration and for treating an immunotolerized IDUA-deficient mammal.
Stated Advantages
Restores alpha-L-iduronidase enzyme activity to wild-type or higher levels in adult brain/CNS.
Widespread restoration of IDUA activity.
Clearance/normalization of glycosaminoglycans (GAG) in brain regions.
Improvement with immunosuppression and/or immunotolerization in the disclosed context.
Documented Applications
CNS-directed therapy for mucopolysaccharidosis type I (MPS I) / alpha-L-iduronidase deficiency by delivering an rAAV9 or rAAVrh10 vector encoding alpha-L-iduronidase, including cisterna magna administration.
Proof-of-principle in adult IDUA-deficient immunocompetent mice with outcomes including restoration of IDUA activity and clearance/normalization of GAG in brain regions.
Additional improvement in the disclosed context with immunosuppression and/or immunotolerization.
CNS delivery routes include intrathecal (cisterna magna/lumbar), intracerebroventricular/intracranial, endovascular administration, and intranasal administration.
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