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Publication Number
US-12377074-B2
Publication Date
2025-08-05
Expiration Date
Abstract
The present invention is directed to a novel treatment for Wolfram Syndrome or heterozygous wolframin, to methods of treatment in order to delay, inhibit, ameliorate and/or reduce the likelihood of symptomology of a patient with Wolfram Syndrome or heterozygous wolframin.
Core Innovation
Wolfram syndrome is described as a progressive, typically fatal disorder in mid-adulthood driven by WFS1 (wolframin) mutations with multisystem manifestations, including diabetes mellitus and diabetes insipidus, optic atrophy, hearing loss, and psychiatric and neurologic dysfunction. The disclosed approach is presented as a disease-modifying therapy that aims to delay, inhibit, or ameliorate symptoms in Wolfram syndrome and heterozygous wolframin/WFS1-related disorder.
The described mechanism centers on NCS1-mediated calcium signaling and calpain activation in response to wolframin and NCS1 interaction. WFS1 loss is described as causing elevated resting cytosolic calcium, reduced ATP-evoked ER-to-cytosol calcium release, impaired ER-mitochondrial calcium transfer, increased calpain activity, and decreased pAKT/insulin signaling, contributing to reduced cell survival and insulin secretion, and hypersensitivity to hyperglycemia.
The document further states that a calpain inhibitor XI and ibudilast (AV411) rescue calcium dysregulation, viability, and glucose-stimulated insulin secretion in WFS1-deficient INS1 cells, and that NCS1 overexpression also rescues calcium homeostasis. The summary also describes a CRISPR-generated WFS1-KO model validated by Western blot and calcium imaging.
Claims Coverage
The partial content contains four independent claims covering treatment of Wolfram syndrome or WFS1 disorder using a structure-defined compound, treatment of a psychiatric disorder associated with heterozygous wolfram using ibudilast or AV1013, treatment of Wolfram syndrome using ibudilast, and treatment of a symptom associated with WFS1 disorder using a structure-defined compound. The claim sets define inventive coverage around specific compound embodiments and therapeutic symptom effects, including psychiatric symptom subsets.
Structure-defined compound for treating Wolfram syndrome or WFS1 disorder
A method of treating Wolfram syndrome or WFS1 disorder by administering an effective amount of a compound according to the chemical structure, wherein R1 is a C1-C6 alkyl, R2 is a C1-C6 alkyl or a group where RC is independently H or C1-C3 alkyl, and i is 0, 1, 2 or 3, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Ibudilast or AV1013 composition for psychiatric disorder associated with heterozygous wolfram
A method of treating a psychiatric disorder associated with heterozygous wolfram by administering an effective amount of a composition comprising ibudilast or AV1013.
Ibudilast for treating Wolfram syndrome
A method of treating Wolfram syndrome by administering an effective amount of ibudilast.
Structure-defined compound for treating a symptom associated with WFS1 disorder
A method of treating a symptom associated with WFS1 disorder by administering an effective amount of a compound according to the chemical structure wherein R1 is a C1-C6 alkyl group, R2 is a C1-C6 alkyl or a group where each RC is independently H or C1-C3 alkyl, and i is 0, 1, 2 or 3, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Across the independent claims, treatment coverage is grounded in administering an effective amount of either a structure-defined compound or specific named actives, ibudilast and AV1013, to treat Wolfram syndrome/WFS1 disorder and to address WFS1-associated symptoms, including psychiatric disorder indications linked to heterozygous wolfram.
Stated Advantages
Delay, inhibit, or ameliorate at least one symptom of Wolfram syndrome or WFS1 disorder.
Treat psychiatric disorders associated with heterozygous wolfram.
Documented Applications
Treating Wolfram syndrome or WFS1 disorder in a patient in need.
Treating a psychiatric disorder associated with heterozygous wolfram.
Treating Wolfram syndrome with ibudilast.
Treating a symptom associated with WFS1 disorder, including symptoms such as sensorineural hearing loss, diabetes mellitus, a psychiatric disorder, and variable optic atrophy.
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