Treatment for skeletal diseases caused by intracellular protein trafficking defects
Inventors
Kondo, Yuji • Fu, Jianxin • Wang, Hua • Wierenga, Klaas • Gaffney, Patrick M. • Xia, Lijun
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-12031136-B2
Publication Date
2024-07-09
Expiration Date
Abstract
The present invention includes a method of treating a bone disease caused by a intracellular protein trafficking defect comprising: identifying a subject having the bone disease caused by the intracellular protein trafficking defect in a membrane bound transcription factor peptidase, site 1 (MBTPS1) gene; and providing the subject with an effective amount of a composition that bypasses or corrects a defect in MBTPS1 gene expression, gene splicing, or corrects protein trafficking defects in the endoplasmic reticulum and to the lysosome.
Core Innovation
The invention identifies biallelic MBTPS1 (S1P) loss-of-function variants in a pediatric patient with skeletal dysplasia and elevated circulating lysosomal enzymes and elucidates a dual pathogenic mechanism. Impaired S1P-mediated activation of GPT causes defective mannose-6-phosphate modification and increased secretion of lysosomal enzymes that cause extracellular matrix degradation. Impaired S1P-mediated activation of BBF2H7 causes defective unfolded protein response and downregulation of COP-II/mega-vesicle genes SEC23A, TANGO1, SEDLIN and HSP47, resulting in ER retention of collagens, chondrocyte apoptosis and bone defects.
The invention provides therapeutic and diagnostic embodiments that map directly to the claims, including expression vectors expressing MBTPS1 or BBF2H7 (p60) or COP-II-related genes; ER chaperones and BiP inducers; chemical chaperones and HDAC inhibitors; an antisense morpholino oligonucleotide to block cryptic splicing; autophagy inducers; diagnostics based on elevated blood lysosomal enzymes; and screening and evaluation methods. Experimental support [procedural detail omitted for safety] directly support the therapeutic claim elements and mechanism-of-action assertions.
Claims Coverage
One independent claim is present. Three main inventive features are extracted from the independent claim.
Method of treating a bone disease caused by an intracellular protein trafficking defect
A method of treating a bone disease in a human caused by an intracellular protein trafficking defect comprising identifying a human subject having the bone disease caused by the MBTPS1 gene and providing the human subject with an effective amount of a composition that bypasses or corrects a defect in MBTPS1 gene expression, gene splicing, or corrects lysosomal protein trafficking.
Identifying subjects by elevated blood lysosomal enzymes and skeletal dysplasia
Identifying a human subject having the bone disease caused by the MBTPS1 gene comprising elevated levels of blood lysosomal enzymes and skeletal dysplasia.
Therapeutic composition comprising specified chemical chaperones
Providing the human subject with an effective amount of a composition wherein the composition comprises a chemical chaperone selected from phenylbutyrate, glycerol phenyl butyrate, sodium phenyl butyrate, and tauroursodexoycholate (TUDCA).
The independent claim covers a method to treat MBTPS1-related bone disease by identifying subjects with elevated blood lysosomal enzymes and skeletal dysplasia and administering compositions that bypass or correct MBTPS1 expression, splicing, or lysosomal protein trafficking, with specified chemical chaperones recited as the therapeutic compositions.
Stated Advantages
Restoration of MBTPS1 splicing and BBF2H7 activation via an antisense morpholino oligonucleotide (AMO).
PBA treatment reduces ER collagen retention.
Induction of BiP expression by the administered composition improves osteogenicity of mesenchymal stem cells differentiated from iPSCs obtained from the subject.
Diagnostics based on elevated blood lysosomal enzymes to identify affected subjects.
Documented Applications
Treatment of bone disease/skeletal dysplasia caused by intracellular protein trafficking defects in MBTPS1.
Expression vectors expressing MBTPS1, BBF2H7 (p60) or COP-II-related genes (for therapeutic use).
Use of ER chaperones and BiP inducers (e.g., BIX; BiP induction as a therapeutic mechanism).
Use of chemical chaperones and HDAC inhibitors (e.g., phenylbutyrate, glycerol phenyl butyrate, sodium phenyl butyrate, TUDCA, valproic acid, belinostat, panobinostat) as therapeutic embodiments.
Use of an antisense morpholino oligonucleotide (AMO) to block cryptic splicing and restore MBTPS1 splicing and BBF2H7 activation.
Use of autophagy inducers (e.g., Tat-D11, Rapamycin, Metformin) as therapeutic embodiments.
Diagnostics and screening/evaluation methods based on elevated blood lysosomal enzymes.
Use of PBA treatment to reduce ER collagen retention (experimental therapeutic support).
Inducing BiP expression to improve osteogenicity of mesenchymal stem cells differentiated from subject-derived iPSCs.
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