Drug Repurposing Patent Applications January

Abstract

GASTROPROKINETIC AGENTS COULD BECOME ORAL PSORIASIS AGENTS

WO/2024/005132

Title: Pharmaceutical composition

Inventors: Hirase R, Ito H, Yasunaga Y

Applicant: Maruno Co., Ltd., Osaka (Japan)

Published: January 4, 2024

In a truly innovative discovery, the inventors have found that psoriasis might be orally treatable with the gastroprokinetic, mosapride, and other 5-HT₄ receptor agonists. While it is known that immune cells (neutrophils, eosinophils, leukocytes, monocytes, and dendritic cells) express various serotonin receptors, including the 5-HT₄ subtype, the effects of stimulating these receptors can have varying effects on inflammatory cytokine release. On the other hand, immunizing mice pups against the 5-HT₄ receptor induces neonatal lupus, apparently by cross-reactivity with SSA/Ro.¹ This ribonucleoprotein also blocks calcium channels, probably including Ca_v1.4 which promotes TH17-cell functions in inflammatory psoriatic skin.² The presented data were obtained in a mouse model of imiquimod-induced dermatitis, which is the most frequently used murine surrogate model for psoriasis.³ Of all agonists that were investigated, mosapride (which is highly selective for the 5-HT₄ receptor) was most effective; prucalopride, velusetrag, tegaserod, cisapride, renzapride, and others are also claimed.

AN ANTIRETROVIRAL FOR FATTY LIVER DISEASE

WO/2024/005289

Title: Composition containing tenofovir alafenamide for prevention, alleviation, or treatment of nonalcoholic steatohepatitis

Inventors: Sung PS, Roh PR, Park DJ

Applicant: The Catholic University of Korea Industry-Academic Cooperation, Seoul (Korea)

Published: January 4, 2024

Non-alcoholic fatty liver disease (NAFLD), renamed metabolic dysfunction-associated steatotic liver disease (MASLD) in 2023, has become a preferred target for drug development due to its high prevalence and its potential progression to inflamed hepatic steatosis (MASH). Tenofovir alafenamide fumarate (TAF), a prodrug of the nucleotide analog reverse transcriptase inhibitor tenofovir, is a potent antiviral commonly used in hepatitis B or HIV infection that can independently induce fibrosis regression in the liver⁴ and in the lungs.⁵ However, the inventors seem to have been the first to report an effect of TAF treatment on MASLD regression. Two slightly different in vivo MASH mouse models were used: streptozotocin-treated mice were fed either a high-fat, high-cholesterol diet or a choline-deficient, L-amino acid-defined, high-fat diet (CDAHF). The livers of TAF-treated mice showed attenuated hepatic infiltration of activated mononuclear phagocytes (IAIE+/PD-L1+/MerTK+) compared to mock-treated livers; serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride levels of CDAHF-induced animals treated with TAF were also reduced, indicating amelioration of liver injury. Mouse liver immunoblotting showed that the phosphorylation level of Akt was significantly lower in the TAF-treated group than in the mock-treated group. In experiments using sorted human CD14⁺ monocytes stimulated with lipopolysaccharide and/or TAF, the inventors identified reduced levels of phosphorylated Akt in TAF-treated-stimulated monocytes compared to mock-treated ones. For the peer review companion article see Roh et al.⁶

ANALGESIC USES OF A SYSTEMIC INFLAMMATORY RESPONSE SYNDROME DRUG ARE EXPANDED

WO/2024/008131

Title: New use of sivelestat

Inventors: Li W, Cao S

Applicant: Shanghai Huilun Pharmaceutical Co., Ltd., Shanghai (China)

Published: January 11, 224

Sivelestat is a selective and competitive neutrophil elastase inhibitor, approved in Japan and Korea for the treatment of acute lung injury associated with systemic inflammatory response syndrome (SIRS). Network pharmacology suggests that several additional anti-inflammatory targets contribute to its effect.⁷ Heidelberg University had claimed it for the treatment of neuropathic pain in WO/2016/050835 (peer review companion article by Bali and Kuner⁸). The present inventors extend this to other types of pain with inflammatory components, particularly traumatic or postoperative pain. Data are provided showing suppression of mechanical nociceptive hypersensitivity in a rat postoperative pain model. In the rat carrageenan model, sevilastat sodium at 10 mg/kg or 100 mg/kg alone had significant analgesic efficacy in the thermal and mechanical sensitivity domains at 3 h post administration, exhibiting synergy with parecoxib in low dose, and significantly prolonged analgesic activity for up to 6 h. Sivelestat (100 mg/kg) in combination was superior to parecoxib high dose alone. It also reduced paw edema at these doses. Similar observations were made in a rat model of blunt muscle injury.

BEVACIZUMAB FOR FROZEN SHOULDER SYNDROME

WO/2024/020641

Title: Vascular endothelial growth factor inhibitors for the treatment of joint disorders

Inventors: Raniga S

Applicant: Macquerie University, North Ryde (Australia)

Published: February 1, 2024

Adhesive capsulitis (“frozen shoulder”) is a common painful and debilitating joint disorder, especially common among diabetics.⁹ Hypervascularity, microangiopathy, inflammation, and fibrosis of the joint capsule sequentially contribute to the symptoms. Residual pain is one of the most important issues after non-surgical therapy, which is done with anti-inflammatory medications, corticosteroid injections into the glenohumeral joint, and physical therapy. Inflammation and angiogenesis are two tightly linked processes in arthritis, and the dominant angiogenetic factor, vascular endothelial growth factor (VEGF), plays an important role in the inflammation of synovial tissue and joint destruction.¹⁰ The inventors propose a single-centered, open-label, dose-ranging clinical trial (not yet registered at Clinicaltrials.gov as per April 2024) in about 20 patients to assess the safety and efficacy of intra-articular bevacizumab (Avastin^® and generics, a recombinant humanized antiVEGF-A monoclonal antibody broadly used in oncology; 50–200 mg single doses) in adults with adhesive capsulitis. Other clinically used VEGF inhibitors (aflibercept, ranibizumab, and brolucizumab) are also claimed. No animal data are presented.

DRUG REPURPOSING AND ANXIETY BIOMARKER DISCOVERY

WO/2024/025536

Title: Precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs

Inventors: Niculescu AB

Applicant: Indiana University Research and Technology Corp., Indianapolis (USA); The U.S. Government as represented by the Dept. of Veterans Affairs, Washington (USA)

Published: February 1, 2024

Although this patent application primarily focuses on discovering biomarkers for anxiety (a subject that has received much attention recently¹¹), it also serves as an excellent demonstration of how precision medicine can advance drug repurposing. In a cohort of 141 male and 17 female psychiatric participants who had experienced at least one switch between a low anxiety state visit and a high anxiety state visit, the inventors prioritized the list of candidate biomarkers based on blood gene expression changes using a Bayesian-like Convergent Functional Genomics approach. They integrated previous human and animal model evidence in the field and validated it in an independent cohort of subjects with clinically severe anxiety. In the next step, they tested the 95 remaining candidate biomarkers in another independent cohort of subjects to assess their ability to predict anxiety severity state and hospitalizations with anxiety as the primary cause. Analyzing the pathways and networks the biomarkers are involved in, as well as which of the 26 top biomarkers had evidence for involvement in other psychiatric and related disorders, they then analyzed which drugs and natural compounds are an opposite match for the gene expression signatures of the 19 remaining biomarkers, using the Connectivity Map (Broad Institute, MIT). The active ingredients were, ordered by decreasing score: thalidomide, ethoxyquine, estradiol, tetracaine, pirenperone, atropine, methylprostaglandin E2, loperamide, tropicamide, and disopyramide. This could be a potential landmark step toward the diagnosis and therapy, based on available agents, of a disorder that has not seen significant drug approvals since the 1990s. For the peer review companion article, see Roseberry et al.¹²

STIMULANT ABUSE AND PARKINSON’S DISEASE LINKED THROUGH DOPAMINE

WO/2024/028349

Title: Levodopa for preventing addiction

Inventors: Vieubled M, Martin C, Sanchez Lopez D, Mintsa M’Owone DB, Rattenbach R

Applicant: 4P-Pharma, Lille (France)

Published: February 8, 2024

Stimulant addiction has been a constant problem for many years among diverse segments of the population, ranging from healthcare professionals to street addicts. With the increasing diagnosis of attention deficit hyperactivity disorder and its treatment with methylphenidate and related agents, there has been a corresponding increase in abuse,¹³ with current prevalence believed to be approximately 5%–10% of high school students and 5%–35% of college students. In September 2019, the United States Food and Drug Administration published a docket requesting comments for the development of abuse deterrent formulations for prescription stimulants, emphasizing the abuse of methylphenidate as a public health concern.¹⁴ The inventors have discovered that the dopamine precursor, levodopa, can prevent the development of behavioral sensitization induced by the stimulant. The effect of a 17 mg/kg dose (equivalent to a 100 mg human dose) reduced methylphenidate-induced hyperactivity to baseline levels in C57B1/6J mice. Just as in its original use in the treatment of Parkinson’s disease, levodopa can be combined with carbidopa to prevent its rapid degradation in the periphery by aromatic L-amino acid decarboxylase. Similar results were obtained for amphetamine locomotor activity. These results are particularly interesting because sustained drug therapy in Parkinson’s disease has been reported to alter the psychomotor responses to acute challenges with L-dopa and methylphenidate and to cause cross-sensitization.¹⁵ Methylphenidate has been suggested as a potential treatment for Parkinson’s disease.¹⁶

A DISCONTINUED DIPEPTIDE AND A DESMOID TUMOR DRUG FOR BLISTERING DERMATOSIS

WO/2024/028912

Title: Gamma-secretase inhibitors for use in the treatment of inherited epidermolysis bullosa

Inventors: Condorelli AG, Zambruno G, El Hachem D, Castiglia D, Odorisio T

Applicant: Ospedale Pediatrico Bambino Gesu’, Roma (Italy); Fondazione Luigi Maria Monti, Roma (Italy)

Published: February 8, 2024

Epidermolysis bullosa is one of the blistering dermatoses caused by failure of the dermal-epidermal junction. Each of the several subtypes of the inherited form (there is also an autoimmune form) is caused by different mutations within the genes encoding proteins that are involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the cutaneous basement membrane.¹⁷ The recessive dystrophic subtype (RDEB) is caused by loss-of-function mutations in the COL7A1 gene, encoding collagen VII, which ensures skin integrity in response to trauma and shear stress. A previous study by the inventors has shown that the Notch ligand Jag1 and the intracellular form of Notch1 are upregulated in RDEB fibroblasts.¹⁸ They have now found that two γ-secretase inhibitors are able to counteract fibrotic behavior of RDEB fibroblasts: N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester (DAPT), a derivatized alanylphenylglycine dipeptide that has been considered for several diseases but is neurotoxic;¹⁹ and nirogacestat,²⁰ approved in the United States for the treatment of desmoid tumors in November 2023, and awaiting European market authorization at the time of writing (April 2024). The γ-secretase protease complex cleaves multiple transmembrane protein complexes, including Notch, and inhibitors halt the processing of the Notch receptor, which makes the inventors’ choice a logical one. In cell culture experiments, Notch pathway inhibition by DAPT and nirogacestat led to a significant decrease in RDEB fibroblast ability to migrate into the cell-free area with respect to non-treated cells. While nirogacestat treatment of RDEB fibroblasts for 48 h caused a statistically significant reduction in their proliferation, DAPT had no such effect. Nirogacestat also caused a reduction in TGF-β secretion and extracellular matrix collagen deposition.

A SIROLIMUS GEL FORMULATION FOR FIBROTIC SKIN

WO/2024/034627

Title: Sirolimus-containing topical drug for treating skin hardening in systemic scleroderma

Inventor: Motegi S-I

Applicant: National University Corporation Gunma University, Gunma (Japan)

Published: February 15, 2024

Scleroderma is an autoimmune disorder that is mostly known for hardening of the skin caused by fibrosis and collagen deposition in the dermis, but often it is the early manifestation of a multisystem disorder (systemic sclerosis) with disordered esophageal motility, renal failure, and pulmonary fibrosis. Given the immunosuppressant and antifibrotic effects of sirolimus (rapamycin) and its derivatives such as everolimus (which had been developed and originally approved to suppress organ transplant rejection), it is not surprising that studies were carried out in scleroderma patients; these suggested an efficacy and side effect burden of systemically administered rapamycin that was comparable to methotrexate.^21,22 However, no data on topical formulations have been reported that would have exploited the effect of rapamycin on α2(I) collagen and matrix metalloproteinase 1 in scleroderma dermal fibroblasts.²³ A 0.2% sirolimus gel, liberally applied to mice with skin fibrosis induced by s.c. injections of bleomycin, was effective in reducing fibrosis, skin thickness, and local inflammation. This could certainly avoid most systemic side effects of rapamycin, including suppression of the cellular immune system.

AN OUTDATED INFLUENZA DRUG TREATS SOLID TUMORS

WO/2024/040182

Title: Salts of 2-S- rimantadine and 2-R rimantadine for treating cancer

Inventors: Lumpkin R, Walters D

Applicant: Toragen, Inc., San Diego (USA)

Published: February 22, 2024

Rimantadine, a racemic adamantane derivative, was developed to treat influenza A infection and was the first drug specifically approved for this purpose but is no longer in use because of limited efficacy and resistance development. The R and S enantiomers bind to the viral M2 transmembrane proton channel with approximately equal affinity. The present document claims both enantiomers for the treatment of cancers associated with tumorigenic strains of human papilloma virus (HPV),²⁴ partly based on the effects they have on E5, one of the early proteins in HPV oncogenesis.²⁵ Six mice were inoculated with 5 × 10⁵ AT84-E7/E5 oral squamous carcinoma cells and treated with intraperitoneal injections of 10 mg/kg pure 2-S rimantadine or pure 2-R rimantadine once daily for a total of 7 injections starting on day 8. Mice that received either enantiomer showed statistically significant decreases in tumor size compared to control groups. Identically designed experiments with 1.5 × 10⁵ B16-OVA melanoma cells and 5 × 10⁵ 4T1 breast cancer cells gave similar results. The antitumor effect was decreased in AT-84-E7 tumors, which do not express E5. Significant increases in surface expression of the major histocompatibility complex were observed in multiple cell lines. Cell surface expression of MHC I on E5-positive AT-84-E7 was restored with pure 2-S rimantadine or pure 2-R rimantadine treatment. To confirm activity against human head and neck tumor lines, BrdU incorporation assays and proliferation assays were performed. Significant cell cycle arrest and decreased proliferation with rimantadine alone were observed in the human CAL-27, CAL-33, and SCC-47 squamous cell carcinoma cell lines. Finally, pure 2-S rimantadine or pure 2-R rimantadine induced cell cycle arrest in murine and human cell lines engineered to express HPV16 E5, and functional reversal of HPV E5 oncoprotein effects. — This patent application might have been preempted by a 2020 article from the University of California.²⁶

PREVENTING ALZHEIMER DISEASE BY REDUCING VISCERAL ADIPOSITY

WO/2024/040256

Title: Pharmaceutical combinations and methods for preventing neurodegenerative diseases

Inventors: Juang J-L, Lai R-H

Applicant: National Health Research Institutes, Zhunan Town (China)

Published: February 22, 2024

It is known that obesity and Alzheimer’s disease are correlated.²⁷ This disclosure claims synergistic compositions of insulin sensitizers (glitazones, biguanides, sulfonylureas) and lipid metabolism modulators (thyroid hormone receptor agonists such as triiodothyronine, thyroxine, and Peroxisome proliferator activated receptor alpha [PPAR-α] agonists) for ameliorating deposition of β-amyloid peptides. Male double transgenic APP/PS1 mice (a model of early-onset Alzheimer’s disease) and aged-matched controls underwent whole-body composition analysis with micro-CT imaging at an age of 5 months (i.e., before amyloid deposits appeared in the brain). The average body weight of the APP/PS1 mice was significantly higher than that of the wild-type mice, attributable to increased visceral fat. Brown adipose tissues of the mutant mice were whitening, with a significant increase in the size of adipocytes. Western blot analysis showed decreased levels of uncoupling protein 1, cytochrome c oxidase subunit IV, and voltage-dependent anion channel, suggesting a lower thermogenic potential. Their plasma levels of free thyroxine (T4) were significantly decreased. Impaired glucose metabolism and pro-inflammatory response were also found to be involved. These phenomena could be induced in wildtype mice by injections of Aβ_(1–42) (intraperitoneally three times at an interval of 3 days). Ingenuity pathway analysis of microarray data suggested that LXR-ABCA1 signaling was among the top pathways identified in adiposity induction. A screen of combination use of pioglitazone, glimepiride, metformin, acarbose (a glucosidase inhibitor), and three cholesterol modifiers (simvastatin, fenofibrate, and levothyroxine) was performed. Based on its results, a prospective matched cohort study was conducted with a dataset from the Taiwanese National Health Research Institutes Database that tracked 10,535 subjects using thyroid hormones and thiazolidinediones for 10 years. The combined drugs significantly reduced the risk of developing dementia by 55% compared to 21.7% with triiodothyronine (T3) and 34.4% by thiazolidinediones alone.

A CARDIOVASCULAR COMBINATION DRUG REVERSES METHAMPHETAMINE ADDICTION

WO/2024/040935

Title: Use of sacubitril/valsartan substance in preparation of drug for drug addiction and relapse

Inventors: Liu Y, Li X, Si Z, Quian L, et al.

Applicant: Ningbo University, Ningbo (China)

Published: February 29, 2024

The fixed combination of the neutral endopeptidase inhibitor, sacubitril and the angiotensin receptor blocker, valsartan (marketed as ENTRESTO™), was the first drug to receive broad approval for the treatment of heart failure. It is also used third-line for hypertension. The inventors tested the idea that this drug could have anti-addiction properties, given that chronic administration of valsartan prevents the induction of morphine-analgesic tolerance and dependence in rats,²⁸ and that neutral endopeptidase also degrades enkephalins, the endogenous opiate receptor agonists that are also a pivotal player in psychostimulant addiction.²⁹ Their deliberations were borne out in the conditioned place preference paradigm with methamphetamine-addicted mice, which showed significantly less preference for methamphetamine when treated with ENTRESTO (60 mg/kg/day in gavage), a dose which also had a preventive effect on relapse after methamphetamine withdrawal, and was not addictive itself. The role of angiotensin-II in addictive behavior, and the enhancement of dopamine reuptake kinetics induced by the AT1 receptor blockade by sartan agents, are only beginning to be appreciated.³⁰

OSTEOPOROSIS DRUGS FOR THE WEAKENED HEART

WO/2024/044642

Title: Compositions and methods for treating cardiomyopathies

Inventors: Sadek HA, Wang P, Ahmed MS, Wu JC-M, Sadayappan S

Applicant: The Board of Regents of the University of Texas System, Austin (USA); The Board of Trustees of the Lleland Stanford University, Stanford (USA); University of Cincinnati, Cincinnati (USA)

Published: February 29, 2024

Dilated cardiomyopathy is a condition where one or both ventricles become enlarged and the cardiac muscle weakens, impeding the heart’s pumping action in the absence of ischemia or abnormal loading conditions. It is the leading cause of sudden cardiac death, and the most common indication for heart transplant. It can be genetically driven or acquired (through infections, chemotherapy, endocrinopathies, immune-mediated diseases, and other factors).³¹ The only available treatments are surgical repair of the ventricle or implantation of biventricular pacemakers and cardioverter defibrillators. The inventors claim to have identified a candidate class of drugs that could serve as a functional and structural corrector for the dilated cardiomyopathy phenotype resulting from a deletion of lysine 210 (DeltaK210) in the cardiac troponin T gene: bisphosphonates, the gold standard treatment for osteoporosis. The K210 deletion not only reduces contractility in mutant cardiomyocytes but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness.³² A structure-based drug repurposing approach was used to identify drugs targeting the mutant troponin, AK210: the MMFF94 energy-minimized library of FDA-approved drugs was docked to the hinge region in AK210 and identified five drugs belonging to the bisphosphonates class based on their binding energies and interacting profiles; they bind towards the induced hinge motif at HLNEDQLR via hydrophobic interactions and hydrogen bond interactions. AK210 bound with Ca²⁺ in the presence of risedronate was resolved at 2.6 Å. Echocardiography and magnetic resonance imaging were conducted for 5–6 weeks in a well-established knock-in mouse model³³ prior to the administration of risedronate (150 µg/kg/day, s.c.) for 15 weeks while accounting for left ventricular ejection fraction. Risedronate produced a significant increase in the ejection fraction over the entire-course of administration. A 4-week crossover study showed that risedronate significantly restored the increase in left ventricular ejection fraction (LVEF) % seen after the switch to sham treatment.

THE OLDEST GROWTH FACTOR TREATS A PAINFUL BLADDER DISORDER

WO/2024/045071

Title: Use of epidermal growth factor in preparing medicament for treating interstitial cystitis

Inventors: Lin MY, Chang L-S, Yang J.M, Li Y-C, Chen H-T

Applicant: Good Care Biotech Ltd., Taipei (Taiwan)

Published: March 7, 2024

In interstitial cystitis, a relatively rare bladder disorder that manifests in pelvic pain and urinary frequency, there is an increase in apoptosis and a decrease in proliferation of urinary epithelial cells, implying a change in the dynamic balance of the urinary epithelium of the bladder. Interstitial cystitis has several subtypes, and treatment options have not been standardized.³⁴ Highly concentrated platelet plasma (in preparations that are also not standardized) has been widely used recently, acting through the variety of growth factors and cytokines, which are released from platelets.^35,36 The inventors propose to apply intravesicular instillations of epidermal growth factor, currently used to promote the healing of diabetic foot ulcers and related non-healing wounds, to enhance repair of the damaged and inflamed bladder epithelium. In a rat model of lipopolysaccharide-induced interstitial cystitis, 400 μL of a solution containing 2 μg of EGF or saline per rat were instilled on the day of cystitis induction, and again on days 7 and 14. Upon sacrifice and histology on day 21, hematoxylin and eosin staining results showed that the normal epithelial tissue structure was absent in the tissue sections of lipopolysaccharide (LPS)-induced mesenchymal cystitis, and that the epidermal growth factor (EGF) treatment helped to improve it; Masson’s trichrome staining method showed less fibrosis of bladder tissues by EGF treatment. Abnormal inflammatory cell infiltration and epithelial thickening were reversed by EGF treatment, EGF inhibited production of the oxidative stress biomarker, malondialdehyde while boosting the antioxidant enzymes that are inhibited due to the pathological environment of interstitial cystitis: glutathione peroxidase and superoxide dismutase.

FENOLDOPAM, A DOPAMINERGIC ANTIHYPERTENSIVE, TREATS COMPLICATIONS OF A RARE RENAL DISEASE

WO/2024/052350

Title: Methods and pharmaceutical compositions comprising D₁-like dopamine receptor agonist for the treatment of autosomal dominant polycystic kidney disease

Inventors: Bellen J, Guerrot D

Applicant: Institut National de la Santé et de la Recherche Médicale, Paris (France); Center Hospitalier Universitaire de Rouen, Rouen (France) — University of Rouen, Rouen (France)

Published: March 14, 2024

Affecting 1 in 1,000 to 1 in 2,500 individuals worldwide, autosomal dominant polycystic kidney disease (ADPKD) is one of the “common rare diseases.” Its telltale signs are the multiple renal cysts that increasingly impair kidney function as they grow, but even pediatric patients also develop arterial hypertension,³⁷ and cardiomyopathies are common in later stages of the disease.³⁸ The inventors had reported earlier that these cardiovascular complications of ADPKD are a direct consequence of the presence of mutated polycystins in vascular endothelial cells which show no activation of calcium-dependent endothelial nitric oxide synthase in response to fluid shear stress, a phenomenon that could be acutely compensated by dopamine infusions.³⁹ Their follow-up data, presented here, show that stimulation of the D₁-like family of dopamine receptors, specifically D₅, is responsible. The preferred D₅ agonists are rotigotine (approved for the treatment of Parkinson’s disease as a transdermal patch; a 2-year Phase II clinical study, NCT06291116, has been registered) and the approved antihypertensive fenoldopam for which data obtained in a C57/Bl6J mouse transgenic models with an endothelial cell-specific inducible knockout of Pkd1 (VE-Cadh/Pkd1fl/fll) has been developed. Compared to control mice with maintained endothelial expression of polycystin-1 (Pkd1fl/fl), VE-Cadh/Pkd1fl/fl had a decreased mesenteric artery endothelium-dependent dilatation in response to stepwise increase in flow assessed by arteriography and an increased blood pressure measured by tail-cuff plethysmography. The administration of fenoldopam during 14 days using osmotic minipumps (20 mmol/g/day) improved endothelium-dependent dilatation and normalized blood pressure (p < 0.05 vs. VE-Cadh/Pkd1fl/fl).

A LARGELY FAILED DRUG CLASS REVISITED FOR MUSCLE WASTING

WO/2024/053761

Title: Composition for promoting myoblast proliferation and differentiation containing aldose reductase inhibitor

Inventors: Lee S, Vuong TA

Applicant: Animuscure Inc. (Korea)

Published: March 14, 2024

Aldose reductase inhibitors had originally been developed for the treatment and prevention of diabetic complications because they inhibit the key enzyme in the polyol pathway which is activated under hyperglycemic conditions. Clinical development did not confirm early experiments for the “restat” class of agents, although research continues.⁴⁰ According to the invention, aldose reductase inhibitors as a class can promote muscle regeneration in sarcopenia, cachexia, and muscular dystrophies. Epalestat, tolestat, fidarestat, and sorbinil mildly but significantly promoted growth of C2C12 mouse myoblast cells. With the exception of sorbinil, these also stimulated proliferation of muscle stem cells obtained from adolescent and aged humans at 1 µM, as shown by BrdU staining and Ki67 mRNA expression. All aldose reductase inhibitors also stimulated myoblast differentiation, as indicated by the expression of Akt, and reduced myotrophy-related markers atrogin-1 and MuRF-1 that had been induced in C2C12 cells by 20 h of dexamethasone exposure. Mitochondria-related gene expression was generally increased. The inventors offer no assumptions concerning the mode of action, but a 1993 article reported that aldose reductase inhibitors could ameliorate diabetic myopathy caused by the enhanced polyol pathway.⁴¹ However, there seem to be no such reports in sarcopenia or other non-diabetic myopathies.

GUANOSINE SYNERGIZES WITH AN ALDOSE REDUCTASE INHIBITOR IN PMM2-CDG

WO/2024/064147

Title: Treating congenital disorders of glycosylation

Inventors: Morava-Kozicz E, Kozicz T, Radenkovic S, Ghesquiére B

Applicant: Mayo Foundation for Medical Education and Research, Rochester (USA); VIB VZW, Ghent (Belgium; Katholieke Universiteit Leuven, Leuven (Belgium)

Published: March 28, 2024

This document claims treating the rare disease, phosphomannomutase 2 deficiency (PMM2-CDG; the most common form of congenital N-glycosylation disorders⁴²) with a combination of aldose reductase inhibitors and one or more nucleosides, to increase the level of guanosine diphosphate-mannose, a downstream metabolite of mannose 1-phosphate which is depleted because of the enzyme defect in this rare disease. A team at the Mayo Foundation had already reported epalrestat as a repurposing candidate, revealing this aldose reductase inhibitor (the only such agent approved for the treatment of diabetic neuropathy in some countries) as the first small molecule activator of PMM2 enzyme activity.⁴³ (Also see WO/2021/071965). Indeed disturbed polyol metabolism is a hallmark of PMM2-CDG, where sorbitol is a biomarker for its severity.⁴⁴ The key finding in the present disclosure is that the sugar nucleotide pools are also depleted in this genetic disorder, and that the addition of nucleosides at 30 µM, especially guanosine, synergizes with epalrestat (10 µM) in cultured primary patient fibroblasts. Tracer studies revealed that aldose reductase inhibition rewires glucose metabolism resulting in increased de novo sugar nucleotide synthesis and glycosylation. The findings in fibroblasts were validated in the genetically stable pmm2 mutant zebrafish strain harboring a mutation in an essential splice site (pmm2saI050), which results in a hypomorphic pmm2 allele.

Footnotes

DISCLAIMER

As the sole author of this article, all contributions according to the CRediT taxonomy as stipulated in are exclusively mine. No other persons were involved in preparing this article.

DISCLOSURE STATEMENT

No competing financial interests exist.

FUNDING INFORMATION

No funding was received for this article.

References

Eftekhari

, Roegel

J-C

, Lezoualc’h

, et al. Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotoninergic 5-HT4 receptor. Eur J Immunol, 2001; 31(2):573–579; doi: 10.1002/1521-4141(200102)31:2<573::AID-IMMU573>3.0.CO;2-9

Mars

, Néant

, Leclerc

, et al. Cav1.4 calcium channels control cytokine production by human peripheral TH17 cells and psoriatic skin-infiltrating T cells. J Allergy Clin Immunol, 2022; 149(4):1348–1357; doi: 10.1016/j.jaci.2021.09.030

Chuang

S-Y

, Lin

C-H

, Sung

, et al. Murine models of psoriasis and their usefulness for drug discovery. Expert Opin Drug Discov, 2018; 13(6):551–562; doi: 10.1080/17460441.2018.1463214

Zhao

, Han

, Zhou

, et al. TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways. Hepatol Int, 2020; 14(1):145–160; doi: 10.1007/s12072-019-09997-6

, Zhao

, Zhou

, et al. Tenofovir alafenamide fumarate attenuates bleomycin-induced pulmonary fibrosis by upregulating the NS5ATP9 and TGF-β1/Smad3 signaling pathway. Respir Res, 2019; 20(1):163; doi: 10.1186/s12931-019-1102-2

Roh

, Kim

, Kang

B-Y

, et al. Tenofovir alafenamide alleviates nonalcoholic steatohepatitis in mice by blocking the phosphorylation of AKT in intrahepatic mononuclear phagocytes. Biomed Pharmacother, 2022; 156:113952; doi: 10.1016/j.biopha.2022.113952

Ren

, Deng

, Li

, et al. Possible pharmacological targets and mechanisms of sivelestat in protecting acute lung injury. Comput Biol Med, 2024; 170:108080; doi: 10.1016/j.compbiomed.2024.108080

Bali

, Kuner

. Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component. PAIN, 2017; 158(11):2243–2258; doi: 10.1097/j.pain.0000000000001032

Struyf

, Mertens

, Navarro-Ledesma

. Causes of shoulder dysfunction in diabetic patients: A review of literature. Int J Environ Res Public Health, 2022; 19(10):6228; doi: 10.3390/ijerph19106228

10.

Semerano

, Duvallet

, Belmellat

, et al. Targeting VEGF-A with a vaccine decreases inflammation and joint destruction in experimental arthritis. Angiogenesis, 2016; 19(1):39–52; doi: 10.1007/s10456-015-9487-0

11.

Maron

, Nutt

. Biological markers of generalized anxiety disorder. Dialogues Clin Neurosci, 2017; 19(2):147–158; doi: 10.3188/7/DCNS.2017.19.2/dnutt

12.

Roseberry

, Le-Niculescu

, Levey

, et al. Towards precision medicine for anxiety disorders: Objective assessment, risk prediction, pharmacogenomics, and repurposed drugs. Mol Psychiatry, 2023; 28(7):2894–2912; doi: 10.1038/s41380-023-01998-0

13.

Clemow

, Walker

. The Potential for misuse and abuse of medications in ADHD: A review. Postgrad Med, 2014; 126(5):64–81; doi: 10.3810/pgm.2014.09.2801

14.

Commissioner O of the. FDA In Brief: FDA Seeks Input on Development and Evaluation of Abuse-Deterrent Formulations of Central Nervous System Stimulants. FDA; 2019. Available from: https://www.fda.gov/news-events/fda-brief/fda-brief-fda-seeks-input-development-and-evaluation-abuse-deterrent-formulations-central-nervous [Last accessed: April 26, 2024 ].

15.

Evans

, Lawrence

, Lees

. Changes in psychomotor effects of L-dopa and methylphenidate after sustained dopaminergic therapy in Parkinson’s disease. J Neurol Neurosurg Psychiatry, 2009; 80(3):267–272; doi: 10.1136/jnnp.2006.108993

16.

Devos

, Moreau

, Delval

, et al. Methylphenidate: A treatment for Parkinson’s disease? CNS Drugs, 2013; 27(1):1–14; doi: 10.1007/s40263-012-0017-y

17.

Ryumina

, Goryunov

, Silachev

, et al. Pathogenetic therapy of epidermolysis bullosa: Current state and prospects. Bull Exp Biol Med, 2021; 171(1):109–121; doi: 10.1007/s10517-021-05182-8

18.

Condorelli

, Logli

, Cianfarani

, et al. MicroRNA‐145‐5p regulates fibrotic features of recessive dystrophic epidermolysis bullosa skin fibroblasts. Br J Dermatol, 2019; 181(5):1017–1027; doi: 10.1111/bjd.17840

19.

Dong

, Huo

, Liang

, et al. Gamma-Secretase Inhibitor (DAPT), a potential therapeutic target drug, caused neurotoxicity in planarian regeneration by inhibiting Notch signaling pathway. Sci Total Environ, 2021; 781:146735; doi: 10.1016/j.scitotenv.2021.146735

20.

Keam

. Nirogacestat: First approval. Drugs, 2024; 84(3):355–361; doi: 10.1007/s40265-024-02002-x

21.

Fried

, Kirsner

, Bhandarkar

, et al. Efficacy of rapamycin in scleroderma: A case study. Lymphat Res Biol, 2008; 6(3-4):217–219; doi: 10.1089/lrb.2008.1006

22.

T-IK

, Khanna

, Furst

, et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: Results from a randomized, single‐blind pilot Study. Arthritis Rheum, 2009; 60(12):3821–3830; doi: 10.1002/art.24986

23.

Tamaki

, Asano

, Kubo

, et al. Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J Dermatol Sci, 2014; 74(3):251–259; doi: 10.1016/j.jdermsci.2014.02.002

24.

Szymonowicz

, Chen

. Biological and clinical aspects of HPV-related cancers. Cancer Biol Med, 2020; 17(4):864–878; doi: 10.2089/2/j.issn.2095-3941.2020.0370

25.

Basukala

, Banks

. The not-so-good, the bad and the ugly: HPV E5, E6 and E7 oncoproteins in the orchestration of carcinogenesis. Viruses, 2021; 13(10):1892; doi: 10.3390/v13101892

26.

Miyauchi

, Sanders

, Guram

, et al. HPV16 E5 mediates resistance to PD-L1 blockade and can be targeted with rimantadine in head and neck cancer. Cancer Res, 2020; 80(4):732–746; doi: 10.1158/0008-5472.CAN-19-1771

27.

Picone

, Di Carlo

, Nuzzo

. Obesity and Alzheimer’s disease: Molecular bases. Eur J Neurosci, 2020; 52(8):3944–3950; doi: 10.1111/ejn.14758

28.

Kaeidi

, Amirteimoury

, Zare

M-S

, et al. Effects of valsartan on morphine tolerance and dependence in rats. Res Pharm Sci, 2021; 16(3):286–293; doi: 10.4103/1735-5362.314827

29.

Mongi-Bragato

, Avalos

, Guzmán

, et al. Enkephalin as a pivotal player in neuroadaptations related to psychostimulant addiction. Front Psychiatry, 2018; 9:222; doi: 10.3389/fpsyt.2018.00222

30.

Basmadjian

, Occhieppo

, Montemerlo

, et al. Angiotensin II involvement in the development and persistence of amphetamine-induced sensitization: Striatal dopamine reuptake implications. Eur J Neurosci, 2024; doi: 10.1111/ejn.16312

31.

Heymans

, Lakdawala

, Tschöpe

, et al. Dilated cardiomyopathy: Causes, mechanisms, and current and future treatment approaches. Lancet, 2023; 402(10406):998–1011; doi: 10.1016/S0140-6736(23)01241-2

32.

Sfichi-Duke

, Garcia-Cazarin

, Sumandea

, et al. Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins. J Mol Cell Cardiol, 2010; 48(5):934–942; doi: 10.1016/j.yjmcc.2010.01.005

33.

C-K

, Morimoto

, Nishii

, et al. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation. Circ Res, 2007; 101(2):185–194; doi: 10.1161/CIRCRESAHA.106.146670

34.

Clemens

, Erickson

, Varela

, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol, 2022; 208(1):34–42; doi: 10.1097/JU.0000000000002756

35.

Jiang

Y-H

, Kuo

Y-C

, Jhang

J-F

, et al. Repeated intravesical injections of platelet-rich plasma improve symptoms and alter urinary functional proteins in patients with refractory interstitial cystitis. Sci Rep, 2020; 10(1):15218; doi: 10.1038/s41598-020-72292-0

36.

Jhang

J-F

, Jiang

Y-H

, Lin

T-Y

, et al. The tumor necrosis factor-α level in platelet-rich plasma might be associated with treatment outcome in patients with interstitial cystitis/bladder pain syndrome or recurrent urinary tract infection. Int J Mol Sci, 2024; 25(1):163; doi: 10.3390/ijms25010163

37.

Massella

, Mekahli

, Paripović

, et al. Prevalence of hypertension in children with early-stage ADPKD. Clin J Am Soc Nephrol, 2018; 13(6):874–883; doi: 10.2215/CJN.11401017

38.

Chebib

, Hogan

, El-Zoghby

, et al. Autosomal dominant polycystic kidney patients may be predisposed to various cardiomyopathies. Kidney Int Rep, 2017; 2(5):913–923; doi: 10.1016/j.ekir.2017.05.014

39.

Lorthioir

, Joannidès

, Rémy-Jouet

, et al. Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans. Kidney Int, 2015; 87(2):465–472; doi: 10.1038/ki.2014.241

40.

Thakur

, Gupta

, Ali

, et al. Aldose reductase: A cause and a potential target for the treatment of diabetic complications. Arch Pharm Res, 2021; 44(7):655–667; doi: 10.1007/s12272-021-01343-5

41.

Cotter

, Cameron

, Robertson

, et al. Polyol pathway-related skeletal muscle contractile and morphological abnormalities in diabetic rats. Exp Physiol, 1993; 78(2):139–155; doi: 10.1113/expphysiol.1993.sp003675

42.

Briso-Montiano

, Del Caño-Ochoa

, Vilas

, et al. Insight on molecular pathogenesis and pharmacochaperoning potential in phosphomannomutase 2 deficiency, provided by novel human phosphomannomutase 2 structures. J Inherit Metab Dis, 2022; 45(2):318–333; doi: 10.1002/jimd.12461

43.

Iyer

, Sam

, DiPrimio

, et al. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis Model Mech, 2019; 12(11):dmm040584; doi: 10.1242/dmm.040584

44.

Ligezka

, Radenkovic

, Saraswat

, et al. Sorbitol is a severity biomarker for PMM2-CDG with therapeutic implications. Ann Neurol, 2021; 90(6):887–900; doi: 10.1002/ana.26245

Drug Repurposing Patent Applications January–March 2024