PTP4A1 as a therapeutic target for fibrotic diseases and disorders including systemic sclerosis
Inventors
Bottini, Nunzio • Sacchetti, Cristiano • Stanford, Stephanie M.
Assignees
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Publication Number
US-11331388-B1
Publication Date
2022-05-17
Expiration Date
Abstract
Methods of treating fibrotic diseases and disorders including Systemic sclerosis (SSc) are provided. Methods include, for example, administering to a subject an effective amount of an antagonist/inhibitor of PTP4A1 protein expression or activity to treat a fibrotic disease or disorder such as SSc, or an associated pathology such as organ or skin fibrosis.
Core Innovation
The patent describes decreasing expression, function, or activity of a protein tyrosine phosphatase 4A1 (PTP4A1) protein to treat fibrosis and systemic sclerosis (SSc). The approach is directed to a subject having fibrosis or systemic sclerosis and is based on administering an agent that decreases PTP4A1 expression, function, or activity. In particular, an antisense oligonucleotide (ASO) is provided that specifically binds a PTP4A1 nucleic acid and inhibits the expression, function, or activity of the PTP4A1 protein.
The document connects PTP4A1 modulation to fibrotic signaling outcomes through TGFβ–SMAD3-associated pro-fibrotic outputs. It reports that PTP4A1 is overexpressed in SSc dermal fibroblasts and that PTP4A1 knockdown reduces pro-fibrotic/TGFβ–SMAD3 signaling outputs, including COL1A2, ACTA2, SMAD3, and αSMA. The patent further reports that PTP4A1 enhances SMAD reporter activation and that PTP4A1 knockout attenuates bleomycin-induced dermal fibrosis.
The patent also describes broader therapeutic concepts for inhibiting or modulating PTP4A1 expression or activity using antisense/acid ASO formats and delivery concepts. It states that the agent can include an antisense oligonucleotide that specifically binds a PTP4A1 nucleic acid and inhibits PTP4A1, and it includes examples of acid ASO formats such as micro-RNA (miRNA), trans-splicing RNA, aptamers, and triplex forming RNA that bind PTP4A1 nucleic acid or protein. The document further includes administration concepts and monitoring based on measuring PTP4A1 nucleic acid/protein/activity, together with diagnostic/monitoring/prognostic approaches linked to SSc-related endpoints.
Claims Coverage
The independent claim is directed to a method for decreasing PTP4A1 expression, function, or activity in a subject with fibrosis or systemic sclerosis using an antisense oligonucleotide (ASO). The inventive features are centered on PTP4A1 targeting by an ASO that specifically binds a PTP4A1 nucleic acid, resulting in inhibition of PTP4A1 expression, function, or activity.
PTP4A1-targeted ASO administration for fibrosis/SSc
A method of decreasing expression, function, or activity of a protein tyrosine phosphatase 4A1 (PTP4A1) protein by administering to a subject having fibrosis or systemic sclerosis a therapeutically effective amount of an agent that decreases expression, function or activity of the PTP4A1 protein.
ASO specifically binding PTP4A1 nucleic acid inhibits PTP4A1
The agent comprises an antisense oligonucleotide (ASO) that specifically binds to a PTP4A1 nucleic acid and inhibits the expression, function or activity of the PTP4A1 protein.
Overall, the claim coverage focuses on ASO-mediated inhibition of PTP4A1 in fibrosis and systemic sclerosis, with dependent claims further narrowing the ASO formats, delivery concepts (including expression cassette/vector types), administration routes, dosing constraints, and optional combination with selected drugs as described in the provided claim set.
Stated Advantages
Decreases expression, function, or activity of PTP4A1 in a subject having fibrosis or systemic sclerosis.
Reduces pro-fibrotic/TGFβ–SMAD3 signaling outputs including COL1A2, ACTA2, SMAD3, and αSMA.
Enhances SMAD reporter activation is reported to be driven by PTP4A1 modulation and is addressed by PTP4A1 targeting.
Attenuates bleomycin-induced dermal fibrosis.
Documented Applications
Therapeutic treatment of fibrosis and systemic sclerosis (SSc) by decreasing PTP4A1 expression, function, or activity using a PTP4A1-targeting ASO.
Mechanism-linked fibrotic signaling context for TGFβ–SMAD3-associated pro-fibrotic outputs (COL1A2, ACTA2, SMAD3, and αSMA).
Attenuation of bleomycin-induced dermal fibrosis as a documented disease model outcome.
Diagnostic/monitoring/prognostic approaches based on measuring PTP4A1 nucleic acid, protein, or activity.
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