WO2023213902A1 - Remofuscine (soraprazan) destinée à être utilisée contre un dysfonctionnement lysosomal et le vieillissement - Google Patents

Remofuscine (soraprazan) destinée à être utilisée contre un dysfonctionnement lysosomal et le vieillissement Download PDF

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WO2023213902A1
WO2023213902A1 PCT/EP2023/061710 EP2023061710W WO2023213902A1 WO 2023213902 A1 WO2023213902 A1 WO 2023213902A1 EP 2023061710 W EP2023061710 W EP 2023061710W WO 2023213902 A1 WO2023213902 A1 WO 2023213902A1
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remofuscin
elegans
worms
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Ulrich Schraermeyer
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KATAIRO GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists

Definitions

  • Remofuscin for use against lysosomal dysfunction and aging
  • the invention relates to new uses of remofuscin.
  • Remofuscin/soraprazan is a ROS generator, specifically a superoxide generator when illuminated with light as described in EP3855181.
  • ROS can degrade Lipofuscin following intravitreal injection with generators of oxygen radicals such as superoxide (Oz), peroxyl (00°), and hydroperoxyl (HOO°), in both monkeys and Abca4 - mice.
  • oxygen radicals such as superoxide (Oz), peroxyl (00°), and hydroperoxyl (HOO°
  • the object of the invention is to provide new uses of remofuscin, including a medical or non-medical use to extend lifespan or improve lysosomal dysfunction.
  • the problem is solved by using remofuscin for pharmaceutical treatment of aging, or by using remofuscin for non-medical anti aging treatment, cosmetic treatment, or as a lifestyle drug or dietary supplement.
  • remofuscin shows a significant anti-aging effect, i.e. remofuscin can be applied systemically with a positive net effect on lifespan.
  • This effect surprisingly appears to require no melanin or light, and is stronger than detrimental effects that are mediated by the remofuscin ROS chemistry on aging.
  • remofuscin can extend lifespan by stimulating the expression of lysosomal lipase genes and/or lysosomal lipid chaperone genes, subsequently increasing the expression levels of the genes involved in xenobiotic detoxification through nuclear hormone receptors and thereby extending lifespan.
  • remofuscin can shift energy metabolism from glucose to lipid oxidation, resulting in the upregulation of beta-oxidation genes and reduces the production of ROS, thus contributing to lifespan extension.
  • the lipid catabolism rate increases to supply energy, and lipid catabolism generates lipid metabolites that mediates lipotoxicity.
  • remofuscin is used against lysosomal dysfunction.
  • the disclosure of the invention is not limited to the compound remofuscin but also applies to tetrahydropyridoethers in general.
  • Fig. 1 Effect of remofuscin on the lifespan of C. elegans (N2). Worms at the L4 stage concentrations of remofuscin. The survival rates were calculated using the Kaplan- Meier method. *p ⁇ 0.05, ***p ⁇ 0.001, log-rank test, compared with the NC.
  • Fig. 2 Effect of remofuscin on aging biomarkers in C. elegans (N2). Three-day-old (day 1 of the adult stage) C. elegans fed on an E. coli OP50 lawn were transferred onto fresh mNGM plates containing E. coli OP50 and various concentrations of remofuscin, and the body lengths of 10 worms from each group were measured (A). The pumping rate in the terminal bulb was measured for 1 min every 48 h from day 4 to day 10, and the mean rate of 15 worms from each group was determined (B). *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, Student’s t-test, compared with the NC.
  • Fig. 3 Accumulation of lipofuscin in remofuscin-treated C. elegans (N2).
  • B The lipofuscin fluorescence in the worms was quantified using ImageJ software. Ten worms from each group were used for the measurements. *p ⁇ 0.05, ***p ⁇ 0.001 , Student’s t-test, compared with the NC.
  • Fig. 4 ROS levels in remofuscin-treated C. elegans (N2). The relative ROS levels were measured after 14 days of treatment with remofuscin. The fluorescence signal in each group (more than 80 worms for each measurement) was normalized to the protein concentration in the group. **p ⁇ 0.01, Student’s t-test, compared with the NC.
  • Fig. 5 Differential gene expression between the negative control and 200 ⁇ M remofuscin-treated groups as determined by RNA microarray analysis.
  • DEG analysis software (ExDEGA v.1.6.8, Ebiogen, KOR) was used to display the gene expression data as a volcano plot (A).
  • the genes in the boxes are related to xenobiotic detoxification shown in Table 2 (fold change > 2.0 and p ⁇ 0.05).
  • the DAVID functional annotation tool was used to analyze the gene ontology terms (B), and the biological processes associated with the DEGs revealed by microarray analysis are shown as a pie chart (C).
  • Fig. 6 Expression levels of genes related to xenobiotic metabolism, lysosomes, and NHRs in remofuscin-treated C. elegans. Worms were grown on NGM plates containing 0 ⁇ M and 200 ⁇ M remofuscin for 1 and 5 days, and the gene expression levels were measured by qPCR. *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001, Student’s t-test, compared with the NC (0 ⁇ M remofuscin) on each day.
  • Fig. 7 Expression levels of ech-9 and cyp-35A subfamily members in wild-type (N2) and nhr-234 mutant C. elegans.
  • the worms were grown on NGM plates containing 0 ⁇ M and 200 ⁇ M remofuscin for 5 days, and the gene expression levels were measured by qPCR.
  • Fig. 8 Predicted mechanism by which remofuscin extends the C. elegans lifespan.
  • a lysosomal lipase, LI PL-1 activates lipid catabolism, similar to that in a diet restriction (DR)-like state, thereby decreasing the ROS levels and subsequently activating the xenobiotic detoxification process.
  • This sequence ultimately extends the lifespan of remofuscin-treated C. elegans.
  • the broken line shows the predicted route based on the previously reported pathway (Chamoli et al., 2014)
  • remofuscin significantly (p ⁇ 0.05) extended the lifespan e.g. of C. elegans (N2) compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms.
  • genes related to lysosomes lipl-1 and lbp-8
  • a nuclear hormone receptor nhr-234
  • fatty acid beta-oxidation ech-9
  • xenobiotic detoxification cyp-34A1 , cyp-35A1 , cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp- 35C1 , gst-28, and gst-5) were increased in remofuscin-treated worms.
  • remofuscin failed to extend the lives of C.
  • elegans with loss-of-function mutations (lipl- 1 , lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1 , cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), showing that these genes are associated with lifespan extension in remofuscin-treated C. elegans.
  • remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.
  • remofuscin stimulates the expression of the lysosomal lipase gene lipl-1 and the lysosomal lipid chaperone gene lbp-8, subsequently increasing the expression levels of the genes involved in xenobiotic detoxification through nuclear hormone receptors and thereby extending the C. elegans lifespan.
  • microarray and qPCR analyses of remofuscin-treated worms in a DR-like state revealed that genes related to lysosomes (lipl-1 and lbp-8), beta-oxidation (echo-9), and xenobiotic detoxification (cyp-34A1 , cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) are upregulated, which prevented damage caused by lipid metabolites.
  • C. elegans has 8 lysosomal lipases, LI PL-1 to LI PL-8, among which LI PL-4 plays a role in the lifespan extension of C. elegans (Folick et al., 2015).
  • LI PL-4 Overexpression of LI PL-4 induces the expression of the lipid chaperone protein LBP-8, and mitochondrial beta- oxidation is activated via NHR-49 and NHR-80 to promote lipid catabolism.
  • ROS in mitochondria mtROS
  • the LI PL-4 and LBP- 8 signaling pathways induce antioxidant targets and oxidative stress tolerance, thereby extending the C. elegans lifespan (Ramachandran et al., 2019).
  • remofuscin did not increase the expression level of jun-1 in C. elegans.
  • the C. elegans genes directly or indirectly involved in lipid catabolism, especially LIPL-1 respond to the DR state and control lipid metabolism (O'Rourke and Ruvkun, 2013).
  • nhr-49 and nhr- 27 play roles in the longevity of C. elegans by reducing the mitochondrial electron transport chain (Khan et al., 2013). Unlike mammals, which have only 48 NHR genes, C. elegans has 284 NHR genes that play roles in various processes, including lipid and xenobiotic metabolism.
  • NHR-49 a homolog of mammalian hepatocyte nuclear factor 4 (HNF4) that functions similarly to peroxisome proliferator-activated receptors (PPARs), is known to transcriptionally regulate many genes related to betaoxidation, including acyl-CoA synthetase, enoyl-CoA hydratase, and carnitine palmitoyl transferase (Pathare et al., 2012; Van Gilst et al., 2005).
  • acyl-CoA synthetase acyl-CoA synthetase
  • enoyl-CoA hydratase enoyl-CoA hydratase
  • carnitine palmitoyl transferase PARs
  • nhr-49 gene Although the expression level of the nhr-49 gene was not increased, that of ech-9 was increased in C. elegans treated with remofuscin. In addition, the nhr-49 deletion mutant failed to extend the lifespan of remofuscin-treated worms, indicating the possible role of NHR-49 in the longevity of remofuscin-treated C. elegans.
  • the gene expression of nuclear receptor NHR-234 which is known to cooperate with NHR-49, was significantly upregulated in remofuscin-treated C. elegans and that the nhr-234 mutant failed to extend the lifespan of the worms.
  • NHR-234 with or without NHR-49 plays a role in the longevity of remofuscin-treated worms by regulating ech-9 expression and thereafter altering the expression of genes related to xenobiotic detoxification.
  • Endogenous lipofuscin the lipid-containing product resulting from the oxidation of unsaturated fatty acids composed of digested lipid-containing lysosomal residues, accumulates over time and can be a xenobiotic.
  • remofuscin acts as an exogenous xenobiotic agent.
  • Dependence on fatty acid oxidation for energy sources leads to the formation of lipophilic endotoxins and, in turn, activates xenobiotic detoxification genes (Lindblom and Dodd, 2006; McElwee et al., 2004).
  • phase I cytochrome p450 enzymes (CYPs) chemically modify endotoxins
  • phase n UDP-glucuronosyl transferases and glutathione S-transferases (GSTs) make them more soluble
  • phase III modified endotoxins are emitted into the extracellular space by ATP-binding cassette transporters
  • NHR-8 is required for xenobiotic resistance and may regulate the expression of cytochrome P450 genes in C. elegans (Lindblom et al., 2001), AHR-1, which is related to CYP-35A subfamily members, regulates lipid signaling (Aarnio, 2014), and PHA-4 induces the expression of xenobiotic detoxification genes (Chamoli et al., 2014).
  • nhr-8 deletion mutants failed to extend the lifespan of remofuscin-treated worms, which means that genes related to xenobiotic detoxification activated by remofuscin conferred C. elegans with longevity.
  • Fig. 8 a pathway that is associated with lifespan extension in remofuscin-treated C. elegans is disclosed in Fig. 8. Remofuscin increases the expression of lysosomal lipase and induces lipid catabolism (beta-oxidation), subsequently activating the xenobiotic detoxification response and extending the C. elegans lifespan.
  • remofuscin-treated worms enter a DR-like state by decreasing their pharyngeal pumping rate, which is followed by a reduction in ROS levels through fatty acid beta-oxidation, thereby contributing to their lifespan extension. Lysosomal signaling from LIPL-4 to LBP-8 followed by NHR-49 and NHR-80 promotes the longevity of C. elegans (Savini et al., 2019); however, the signal herein was observed from LIPL-1 to LBP-8, followed by NHR-234 and/or NHR-49.
  • Remofuscin is also known as a potent and reversible inhibitor of the H A +/K A +ATPase proton pump in cynomolgus monkeys (Julien and Schraermeyer, 2012). Although the proton pump which is inhibited by remofuscin is not present in the RPE in the eyes of human, proton pump inhibitors are known to increase the lysosomal pH, thereby activating transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, and inducing lysosomal exocytosis and autophagy (Nociari et al., 2017).
  • TFEB transcription factor EB
  • Remofuscin binds to lipofuscin (Julien-Schraemeyer et al., 2020) and is a superoxide generator when illuminated with light (Katairo and Takeda, 2021). Superoxide might help to degrade the polymeric lipofuscin into smaller units which then are transported out of the lysosomes by exocytosis.
  • TFEB is an ortholog of HIH-30 in C. elegans, and HIH-30 is known to function as a transcription factor of lipl-1 in C. elegans in a DR-like state (O'Rourke and Ruvkun, 2013).
  • LIPL-1 degrades lipids in the lysosomal lipophagy process.
  • Lifespan extension derives from many factors, such as diet restriction (DR) and strengthened immunity, in a wide range of taxa ranging from yeast to primates (Hwangbo et al., 2020; Kurz and Tan, 2004).
  • DR diet restriction
  • Aging induces morphological and metabolic changes, such as body size alteration and lipofuscin accumulation, which thus serve as biomarkers of aging (Pincus and Slack, 2010).
  • Lipid metabolism is also altered over time, and aging and longevity are thus regulated by lipid signaling (Mutlu et al., 2021). Many of the pathways regulating lifespan are linked to lipid metabolism, and lipids act as signaling molecules in longevity signaling pathways.
  • DR is one of the most influential environmental interventions that extends the lifespans of a variety of species (Greer et al., 2007). Beta-oxidation genes are upregulated in a DR- like state, consequently reducing the amount of stored fat, which leads to lower reactive oxygen species (ROS) levels. ROS are known as a major cause of aging and oxidative damage (Page et al., 2010).
  • C. elegans Chamoli et al., 2014.
  • lysosomes play an important role in the early catabolic steps of lipid degradation (Settembre and Ballabio, 2014).
  • C. elegans has eight lysosomal lipases, LIPL-1 to LIPL-8 (Seah et al., 2016); LIPL-4 has been extensively studied because it plays important roles in autophagy, fat metabolism, and lysosomal activity, which are linked to longevity in C.
  • lipl-1 is the most upregulated in the fasting state, and its sequence is similar to that of human lysosomal acid lipase (BLAST scores 9e-78) (O'Rourke and Ruvkun, 2013). Remofuscin extends the lifespan of C. elegans
  • Remofuscin significantly increased the MLS of wild-type C. elegans (N2) in a dose-dependent manner compared with that of the NC (0 ⁇ M remofuscin) (Table 1).
  • the MLSs of C. elegans (N2) treated with 50 ⁇ M, 100 ⁇ M, and 200 ⁇ M remofuscin were increased by 9.9%, 14.6%, and 20.4%, respectively.
  • the survival rates of the worms treated with remofuscin were higher than those of the untreated worms after 5 days (Fig. 1).
  • age-related biomarkers body length and pharyngeal pumping rate
  • a reduced pharyngeal pumping rate indicates a decrease in feeding, which can induce a DR-like state (Onken and Driscoll, 2010).
  • the pharyngeal pumping rates of the remofuscin-treated groups were significantly (p ⁇ 0.05) decreased compared with that of the NC group (Fig. 2B). Regardless of whether C. elegans was treated with or without remofuscin, the pharyngeal pumping rate decreased until 6 days; however, the pumping rates of worms treated with 100 ⁇ M and 200 ⁇ M remofuscin at 8 and 10 days were nearly similar or even higher than those at 6 days. In contrast, the pharyngeal pumping rate of the NC group continuously decreased over 10 days.
  • Lipofuscin accumulation is decreased in remofuscin-treated C. elegans
  • Lipofuscin accumulation serves as a biomarker of aging, and remofuscin significantly decreased the lipofuscin levels in C. elegans treated with 100 ⁇ M and 200 ⁇ M remofuscin on day 14 (Fig. 3). These results show that remofuscin affects lifespan extension in C. elegans.
  • GO analysis showed 10 major functional categories in the BP group, 8 categories in the CC group, and 7 categories in the MF group based on the criterion for identifying differentially expressed genes by microarray analysis (fold change > 2.0 and p ⁇ 0.05) (Fig. 5B).
  • Fig. 5B those related to response to xenobiotic stimuli were highly expressed in the 200 ⁇ M remofuscin-treated worms compared with the NC worms.
  • Xenobiotic detoxification is known to affect longevity in C. elegans, and based on the total significance (Fig. 5C), we focused on the genes related to xenobiotic stimulus responses.
  • genes related to xenobiotic metabolism (GO: 0006805) (cyp-13A2, cyp-34A1 , cyp-35A1 , cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1 , gst-28, gst-5, ugt-65, pgp-14, and folt-2) were significantly (p ⁇ 0.05) increased (>2-fold) compared with those in the NC group (0 ⁇ M remofuscin) as determined by microarray analysis (Table 2).
  • Table 2 shows that the expression levels of genes related to xenobiotic metabolism, especially cyp35A subfamily genes, were significantly increased in remofuscin-treated worms compared with NC worms (Fig. 6). Usually, the gene expression levels were higher at 5 days than at 1 day. In addition, the expression levels of lipl-1, lbp-8, and echo-9 were significantly increased in remofuscin-treated worms. Although the differences were not statistically significant, the levels of several nuclear hormone receptor (NHR) genes, transcription factors of cytochrome p450 family genes, were increased by more than 2-fold as determined by microarray analysis (Table S2). Among them, the levels of only nhr-210 and nhr-234 were significantly increased in remofuscin-treated worms compared with the NC worms as determined by qPCR analysis (Fig. 6)
  • loss-of function mutants for genes related to xenobiotic detoxification were used for longevity assays.
  • the loss-of function mutants available from the CGC and NBRP were selected based on the qPCR results.
  • the expression levels of the transcription factor genes (nhr-49, nhr-8, ahr-1, and pha-4) related to lipid metabolism and xenobiotic stimulus responses in C. elegans were not upregulated in remofuscin- treated worms compared with the NC (Fig.
  • loss-of function mutants were used to assess lifespan extension based on previous reports that they regulate the expression of genes related to lipid and xenobiotic metabolism (Chamoli et al., 2014; Folick et al., 2015; Lindblom et al., 2001 ; Menez et al., 2019; Ramachandran et al., 2019).
  • Remofuscin treatment failed to extend the lifespans of worms exhibiting loss-of-function mutations of genes related to lipid metabolism (lipl-1 and lbp-8) and xenobiotic detoxification (cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5) (Table 3, Fig. S2).
  • remofuscin failed to extend the lifespan of C. elegans harboring transcription factor (nhr-49, nhr-8, and nhr-234) mutants but not that of worms with the nhr-210 mutant.
  • the ahr-1 and pha-4 deletion mutants extended the lifespans of 100 ⁇ M and 200 ⁇ M remofuscin-treated worms, respectively, their overall MLSs were decreased by remofuscin treatment compared with the wild type.
  • NHR-234 cooperates with NHR-49 to induce the transcription of target genes related to lipid metabolism.
  • Remofuscin-treated nematodes upregulated nhr-234 expression compared with that in the control group, and the nhr-234 mutant failed to extend the lifespan of the worms.
  • NHR-234 To investigate the effect of NHR-234 on the expression of genes related to lipid metabolism and xenobiotic detoxification proposed to be downstream of NHR-234 in C.
  • elegans treated with remofuscin the expression levels of ech-9, cyp- 35A1, cyp-35A2, cyp-35A3, cyp-35-A4, and cyp-35A5 in the nhr-234 deletion mutants were analyzed by qPCR.
  • Escherichia coli OP50 was obtained from the Caenorhabditis Genetics Center (CGC, USA) of the University of Minnesota and used as a food for C. elegans.
  • E. coli OP50 was grown in Luria-Bertani (LB) broth (Ambrothia, Daejeon, Korea) at 37 °C overnight with shaking, collected by centrifugation at 3,000x g for 10 min, washed in sterile M9 buffer, and diluted to a final concentration of 0.1 mg (wet weight) per microliter in M9 buffer (Zhao et al., 2013).
  • Worms were maintained and propagated in peptone-free modified nematode growth medium (mNGM) at 25 °C according to standard techniques (Stiernagle, 2006).
  • E. coli OP50 was spread on mNGM in 90-mm-diameter Petri dishes as food for the worms.
  • a sodium hypochlorite-sodium hydroxide solution (Sigma Aldrich, St. Louis, MO, USA) was used to obtain viable eggs as previously described (Sulston and Hodgkin, 1988). The eggs were transferred onto fresh mNGM plates seeded with E.
  • Remofuscin (kindly provided by Professor Ulrich Schraermeyer, Universitat Tubingen, Tubingen, Germany) was dissolved in dimethyl sulfoxide (DMSO, Sigma Aldrich) and administered final concentrations of 0 ⁇ M (control), 50 ⁇ M, 100 ⁇ M, and 200 ⁇ M. An equal amount of DMSO (final concentration, 0.2%) was added as the control.
  • 5-Fluoro- 2'-deoxyuridine (FUdR, Sigma Aldrich) (50 ⁇ M) was added to the plates (Gruber et al., 2009), which were then seeded with E. coli OP50. The C.
  • elegans mean lifespan (MLS) assay was conducted by transferring 15 young adult (L4 stage) worms onto mNGM/FUdR plates containing E. coli OP50 and treated with remofuscin at the indicated concentrations. The plates were incubated at 25 °C, and the live and dead worms were counted every 24 h. Worms were considered “dead” when they did not respond to a gentle touch with a worm picker. Nematodes that crawled off the plates and died in a non-natural manner, such as by bagging or adhering to the plate wall, were not included in the analysis (censored) (Schmeisser et al., 2013). The worms were transferred every two days to maintain a sufficient food source. All experiments were conducted three times independently at least in triplicate, and more than 100 worms were scored.
  • the MLS was estimated using the following equation (Wu et al., 2006):
  • j is the age (day)
  • dj is the number of worms that died during the day interval (xj, x_(j+1))
  • N is the total number of worms.
  • SE standard error
  • Worms at the L4 stage (day 1 of the adult stage) were transferred onto mNGM plates (60 mm Petri dish) containing various concentrations of remofuscin and seeded with 5 mg (wet weight) of E. coli OP50 in M9 buffer.
  • the plates were incubated at 25 °C, and the body lengths of live worms were measured every 24 h until 6 days of age. In total, 10 worms per group were measured.
  • C. elegans were imaged with a stereomicroscope (Olympus SZ61, Tokyo, Japan) and a ToupCam (UCMOS05100KPA, ToupTek, Hangzhou, China), and the images were analyzed by using ToupCam software. The area of the worm’s projection was estimated automatically and used as an index of body length.
  • Three independent experiments were conducted for each group.
  • a pharyngeal pumping rate assay was performed on mNGM plates seeded with E. coli OP50 and treated with various concentrations of remofuscin.
  • Three-day-old worms (L4 stage) were transferred onto mNGM plates containing various concentrations of remofuscin and incubated at 25 °C, and the number of contractions in the terminal bulb of the pharynx was counted every 48 h for 1 min using an Olympus CKX41 inverted microscope (400*).
  • Three independent experiments were conducted, and 15 worms were included in each group for each measurement.
  • the autofluorescence of lipofuscin in 14-day-old adult C. elegans was measured as an aging index. Randomly selected worms from each group were placed onto 5% agar pads coated with 10 mM sodium azide (Junsei Chemical, Tokyo, Japan) in M9 buffer for anesthetization. Images of lipofuscin autofluorescence at a blue excitation wavelength (405-488 nm), which captures 4',6-diamidino-2-phenylindole (DAPI), were acquired with a laser confocal scanning microscope (Olympus 1x81 -FV1000) (Zhao et al., 2013). Fluorescence was quantified using FV10-ASW1.1 software (Olympus) to measure lipofuscin accumulation. Three independent experiments were conducted, and 10 worms were included in each group for each measurement.
  • the ROS levels in C. elegans treated with 0 ⁇ M, 50 ⁇ M, 100 ⁇ M, and 200 ⁇ M remofuscin were measured for 14 days. Randomly selected worms from each group were washed twice with M9 buffer, after which the supernatant was removed, and the remaining worm pellet was suspended in 100 pL of M9 buffer. The worm pellet (100 pL) and 100 pL of 50 mM 2',7'-dichlorofluorescein diacetate (H2-DCF-DA, Sigma Aldrich) were added to the wells of a black 96-well plate.
  • H2-DCF-DA 50 mM 2',7'-dichlorofluorescein diacetate
  • the ROS levels were measured with a fluorescence microplate reader (SpectraMAX GEMINI EM, Molecular Devices, Sunnyvale, CA, USA) at excitation and emission wavelengths of 485 nm and 520 nm, respectively, at 90 min after activation.
  • the fluorescence signal in each group which included more than 80 worms for each measurement, was normalized to the protein concentration in each group. Three independent experiments were conducted.
  • TRIzol Invitrogen, Carlsbad, CA, USA
  • the synthesis of target cRNA probes and hybridization were performed using an Aligent Lowlnput QuickAmp labeling kit (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer’s instructions.
  • Amplified and labeled cRNA was purified on a cRNA Cleanup Module (Agilent Technologies), and labeled cRNA targets were quantified using an ND-1000 spectrophotometer (NanoDrop Technologies, Inc., Wilmington, DE, USA). After checking the labeling efficiency, the cRNA was fragmented by adding 10X blocking agent and 25X fragmentation buffer and incubating at 60 °C for 30 min. The fragmented cRNA was resuspended in 2X hybridization buffer and directly pipetted onto assembled C. elegans oligo microarrays (Agilent, 44K). The arrays were hybridized at 65 °C for 17 h using a hybridization oven (Agilent Technologies).
  • the hybridized microarrays were washed according to the manufacturer’s protocol (Agilent Technologies). The hybridized images were scanned using an Agilent DNA microarray scanner and quantified with Feature Extraction 10.7 software (Agilent Technologies). Raw intensity data were globally normalized (Cheadle et al., 2003). All data normalization and selection of differentially expressed genes (fold change) were performed using GeneSpring GX 7.3.1 (Agilent Technologies). The criterion for the identification of genes with significantly altered expression was a p value ⁇ 0.05 compared with the negative control. The RNA sequencing data were deposited in the NCBI Gene Expression Omnibus (GEO) database (accession code: GSE144059).
  • GEO Gene Expression Omnibus
  • TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants. Aging (Albany NY) 5, 741-758.
  • the transcription factor NHR-8 A new target to increase ivermectin efficacy in nematodes. PLoS Pathog. 15, e1007598.

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Abstract

L'invention concerne la remofuscine destinée à être utilisée contre le vieillissement, un dysfonctionnement lysomal, ou dans la stimulation de l'expression de gènes de lipase lysosomaux et/ou de gènes chaperons de lipides lysosomaux, et à être utilisée pour augmenter les niveaux d'expression des gènes impliqués dans la détoxification xénobiotique par l'intermédiaire de récepteurs d'hormones nucléaires.
PCT/EP2023/061710 2022-05-03 2023-05-03 Remofuscine (soraprazan) destinée à être utilisée contre un dysfonctionnement lysosomal et le vieillissement Ceased WO2023213902A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015121441A1 (fr) * 2014-02-13 2015-08-20 Katairo Gmbh Procédés permettant de déterminer des composés ou compositions pour le traitement de maladies liées à la lipofuscine, et composés ou compositions
WO2023034553A1 (fr) * 2021-09-02 2023-03-09 Jcr Pharmaceuticals Co., Ltd. Composé thérapeutique contre la lipofuscinose neuronale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015121441A1 (fr) * 2014-02-13 2015-08-20 Katairo Gmbh Procédés permettant de déterminer des composés ou compositions pour le traitement de maladies liées à la lipofuscine, et composés ou compositions
EP3855181A1 (fr) 2014-02-13 2021-07-28 Katairo GmbH Composés pour le traitement de maladies associées à la lipofuscine
WO2023034553A1 (fr) * 2021-09-02 2023-03-09 Jcr Pharmaceuticals Co., Ltd. Composé thérapeutique contre la lipofuscinose neuronale

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