Methods and compositions for treating urea cycle disorders
Inventors
Sehgal, Alfica • Sigova, Alla A. • Zlobine, Igor • Schwartz, Brian E. • Bumcrot, David A. • Rajagopal, Vaishnavi • Jung, Yun Joon • Nishi, Yuichi
Assignees
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Publication Number
US-11266655-B2
Publication Date
2022-03-08
Expiration Date
Abstract
Provided are methods and compositions for the treating a patient with a urea cycle disorder. Methods and compositions are also provided for modulating genes encoding enzymes that participate in the urea cycle by altering gene signaling networks.
Core Innovation
The disclosed invention provides methods for treating urea cycle disorders involving partial OTC function due to OTC mutations by increasing OTC gene expression. The approach includes increasing CPS1 expression in a cell and in a subject, and applies to cells or subjects harboring an OTC mutation associated with a partial reduction of OTC function.
In the disclosed methods, the CPS1 expression increase is achieved by contacting a cell or administering to a subject an effective amount of a compound that increases CPS1 expression and inhibits HSP90. The disclosed examples include compounds that inhibit HSP90, including EC144 and 17-AAG.
The disclosure further describes related urea cycle gene targets, including CPS1, OTC, ASS1, ASL, NAGS, ARG1, SLC25A15/ORNT1, and SLC25A13/citrin, and includes RNA-seq analysis, concentration-dependent fold-change datasets, siRNA-mediated upregulation of OTC, mechanistic links involving JAK1 inhibitors and HSP90 inhibition, and ChIP-seq mapping of signaling centers and chromatin marks at urea-cycle gene loci.
Claims Coverage
The independent claims, 2 total, define two inventive methods that share the same core concept: increasing CPS1 expression to thereby increase OTC expression in the context of OTC mutations with partial OTC function. Across the independent claims, there are two principal inventive feature areas: a CPS1-increasing compound that inhibits HSP90, and the context of application either by contacting cells or by administering to a subject.
CPS1-increasing HSP90-inhibiting compound for OTC gene expression in OTC-mutant cells
A method for increasing OTC gene expression in a cell harboring an OTC mutation associated with a partial reduction of OTC function, comprising contacting the cell with an effective amount of a compound that increases CPS1 expression, wherein the compound inhibits HSP90.
CPS1-increasing HSP90-inhibiting compound for OTC expression in OTC-mutant subjects
A method for increasing OTC expression in a subject harboring an OTC mutation associated with a partial reduction of OTC function, comprising administering to the subject an effective amount of a compound that increases CPS1 expression, wherein the compound inhibits HSP90.
Both independent claims are directed to increasing OTC expression by increasing CPS1 expression using an effective amount of a compound that inhibits HSP90, applied either by contacting OTC-mutant cells or by administering the compound to OTC-mutant subjects.
Stated Advantages
Increases OTC gene expression.
Compounds inhibit HSP90 while increasing CPS1 expression.
HSP90 inhibition increases urea production in vitro and increased urea levels in vivo.
Documented Applications
Increasing OTC gene expression in a cell harboring an OTC mutation associated with a partial reduction of OTC function.
Increasing OTC expression in a subject harboring an OTC mutation associated with a partial reduction of OTC function.
siRNA-mediated upregulation of OTC.
Mechanistic links showing JAK1 inhibitors increase OTC/CPS1/urea-cycle gene expression.
Mechanistic links showing HSP90 inhibition increases OTC/CPS1/urea-cycle gene expression and is associated with increased urea production in vitro and increased urea levels in vivo.
ChIP-seq mapping of signaling centers and chromatin marks at urea-cycle gene loci.
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