Method for the treatment of mucopolysaccharidosis type I
Inventors
Ando, Dale • Foo, Cheryl Wong Po • Vaidya, Sagar A. • Wang, Shelley Q.
Assignees
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Publication Number
US-11857641-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Described herein are methods and compositions for treating MPS I (Hurler/Hurler-Scheie/Scheie Syndrome) by administering to the subject a composition comprising a iduronidase (IDUA) polynucleotide. In one aspect, provided is a method of reducing, delaying and/or eliminating one or more of the need for additional treatment procedures, the onset, progression and/or severity of symptoms in a subject with MPS I, by administering to the subject a composition comprising a iduronidase (IDUA) polynucleotide.
Core Innovation
The invention relates to a method of reducing, delaying and/or eliminating the need for additional treatment procedures, the onset, progression and/or severity of symptoms in a subject with MPS I. The method administers a composition comprising first, second and third AAV vectors, wherein the first AAV vector encodes a left ZFN comprising SEQ ID NO: 23, the second AAV vector encodes a right ZFN comprising SEQ ID NO: 26, and the third AAV vector encodes iduronidase (IDUA).
The approach uses an AAV-based composition that encodes targeted genome insertion components and IDUA. The engineered ZFN mediates insertion of a corrective human IDUA transgene at the intron 1 of the albumin locus in hepatocytes, with stable, liver-specific hIDUA expression and secretion to increase active IDUA in plasma and leukocytes. By increasing active IDUA, the document describes a reduction or stabilization of urinary total GAG and specific GAG species, including dermatan sulfate and heparan sulfate.
The disclosure further describes disease-associated genes and treatment definitions for MPS I, including severe and attenuated MPS I, and frames the approach around reducing supportive interventions and/or delaying disease symptom progression. It also describes nuclease systems for targeted genome insertion, including ZFN systems with DNA-binding and cleavage domains and engineered cleavage half-domains, including obligate heterodimers, together with left and right ZFN components.
The documented applications further describe IDUA transgene insertion into safe-harbor loci and example AAV vector constructs, including expression control and nuclease components. The disclosure also addresses limitations associated with the blood-brain barrier and describes co-administered or adjunct measures intended to support CNS-related delivery.
Claims Coverage
The independent claim coverage centers on a three-AAV-vector composition for MPS I, combining left and right ZFN components defined by SEQ ID NO: 23 and SEQ ID NO: 26 with a third AAV vector encoding IDUA, for reducing, delaying and/or eliminating additional treatment procedures and symptom onset, progression and/or severity. Two inventive features are identified in the independent claim set.
AAV vector composition with left ZFN, right ZFN, and IDUA
A composition comprising first, second and third AAV vectors, wherein the first AAV vector comprises a sequence encoding a left ZFN comprising SEQ ID NO: 23, the second AAV vector comprises a sequence encoding a right ZFN comprising SEQ ID NO: 26, and the third AAV vector comprises a sequence encoding iduronidase (IDUA).
Reducing, delaying and/or eliminating MPS I treatment burden and symptoms
A method of reducing, delaying and/or eliminating the need for additional treatment procedures, the onset, progression and/or severity of symptoms in a subject with MPS I by administering the AAV composition comprising the left ZFN, right ZFN, and IDUA.
Overall, the claim coverage is directed to a three-AAV composition combining a specified left ZFN (SEQ ID NO: 23), a specified right ZFN (SEQ ID NO: 26), and an IDUA-encoding AAV vector to reduce or delay the need for additional treatment procedures and to reduce symptom onset, progression, and/or severity in a subject with MPS I.
Stated Advantages
Reduces, delays and/or eliminates the need for additional treatment procedures in a subject with MPS I.
Reduces the onset, progression and/or severity of symptoms in a subject with MPS I.
Increases IDUA activity and/or level as a basis for delaying, reducing, or eliminating additional therapeutic procedures.
Decreases total GAG, dermatan sulfate (DS) GAG, and heparan sulfate (HS) GAG levels in urine as a basis for delaying, reducing, or eliminating additional therapeutic procedures.
Can reduce or delay/eliminate additional treatment procedures including enzyme replacement therapy, bone marrow transplant, and supportive surgical procedures.
Documented Applications
In vivo gene therapy approach for MPS I using engineered ZFN-mediated insertion of a corrective human IDUA transgene to increase active IDUA in plasma and leukocytes.
Reducing, delaying and/or eliminating additional MPS I treatment procedures such as enzyme replacement therapy and/or HSCT/bone marrow transplant and supportive surgeries.
Clinical evaluation using endpoints including IDUA activity, urine GAGs, pulmonary function, 6-minute walk, joint range of motion, spleen/liver volume, and neurocognitive testing (WASI-II).
Use of second-generation ZFN variants (e.g., SB-71557/SB-71728) and potential benefits in patients with albumin SNPs.
A method for treating a subject with MPS I by reducing, delaying and/or eliminating the need for additional treatment procedures and improving symptom onset, progression and/or severity.
A method in which additional therapeutic procedures such as enzyme replacement therapy, bone marrow transplant, and supportive surgical procedures for orthopedic, cardiac, and/or upper airway obstruction may be reduced, delayed and/or eliminated.
Phase I study implementation for a composition involving AAV2/6 SB-IDUA transgene donor and monitoring of IDUA activity and urine GAG in subjects with MPS I/Hurler syndrome [procedural detail omitted for safety].
Monitoring and decision framework to reduce, delay and/or eliminate additional therapeutic procedures in a subject with MPS I, including enzyme replacement therapy, bone marrow transplant, and supportive orthopedic, cardiac, and upper airway surgeries [procedural detail omitted for safety].
IDUA transgene insertion into safe-harbor loci (e.g., albumin/HPRT) and related strategies described as applications.
Episome and secretory-cell strategies described as applications.
Hematopoietic stem cell and RBC production approaches described as applications.
Approaches to address blood-brain barrier limitations described as part of the applications, including defined adjunct mechanisms.
Example AAV vector systems and constructs for IDUA treatment are described, including example left/right ZFN AAVs (SB-47171, SB-47898) and additional ZFN AAVs (SB-71557).
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