Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

Lamer, Sophie Le; Paradis, Stéphanie; Rahmouni, Hidayat; Chaimbault, Corinne; Michaud, Magali; Culcasi, Marcel; Afxantidis, Jean; Latreille, Mathilde; Berna, Patrick; Berdeaux, Alain; Pietri, Sylvia; Morin, Didier; Donazzolo, Yves; Abitbol, Jean‐Louis; Pruss, Rebacca M; Schaller, Sophie

doi:10.1186/1479-5876-12-38

Cited by 32 publications

(38 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TRO40303 (3,5-seco-4-nor-cholestan-5-one oxime-3-ol) was derived from a chemistry optimization program based on the structure of TRO19622 and has pronounced cytoprotective effects and preserves cardiac tissue in a rat model of cardiac ischemia-reperfusion injury (Schaller et al, 2010). These cholesterol oximes access brain after oral administration, are safe, and have moved forward into clinical trials (Le Lamer et al, 2014; Lenglet et al, 2014). They bind to mitochondrial outer membrane proteins, the 18kDa translocator protein (TSPO) and the voltage-dependent anion channel (VDAC, TRO19622 only), reduce oxidative stress-induced mitochondrial permeability transition (mPTP), and the release of pro-apoptotic factors (Bordet et al, 2007; Schaller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

show abstract

Section: Introductionmentioning

confidence: 99%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite identification of small molecule inhibitors of mPT presenting an obvious therapeutic opportunity, the availability and development of such agents remains limited. A number of groups have identified novel molecules modulating mitochondrial propensity for permeability transition30323334353637. However, as yet, reports of positive clinical development are yet to emerge.…”

mentioning

confidence: 99%

Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria

Briston

Lewis

Koglin

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca2+ uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca2+-induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca2+-induced membrane depolarisation and Ca2+ retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature.

show abstract

“…administration in previous studies (Le Lamer et al. ). In a second stage, TRO40303 was administered by i.v.…”

Section: Resultsmentioning

confidence: 72%

TRO40303, a mitochondrial‐targeted cytoprotective compound, provides protection in hepatitis models

Schaller

Michaud

Latyszenok

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

TRO40303 is cytoprotective compound that was shown to reduce infarct size in preclinical models of myocardial infarction. It targets mitochondria, delays mitochondrial permeability transition pore (mPTP) opening and reduces oxidative stress in cardiomyocytes submitted to ischemia/reperfusion in vitro. Because the involvement of the mitochondria and the mPTP has been demonstrated in chronic as well as acute hepatitis, we investigated the potential of TRO40303 to prevent hepatocyte injury. A first set of in vitro studies showed that TRO40303 (from 0.3 to 3 μmol/L) protected HepG2 cells and primary mouse embryonic hepatocytes (PMEH) from palmitate intoxication, a model mimicking steatohepatitis. In PMEH, TRO40303 provided similar protection against cell death due to Jo2 anti-Fas antibody intoxication. Further studies were then preformed in a mouse model of Fas-induced fulminant hepatitis induced by injecting Jo2 anti-Fas antibody. When mice received a sublethal dose of Jo2 at 125 μg/kg, TRO40303 pretreatment prevented liver enzyme elevation in plasma in parallel with a decrease in cytochrome C release from mitochondria and caspase 3 and 7 activation in hepatic tissue. When higher, lethal doses of Jo2 were administered, TRO40303 (10 and 30 mg/kg) significantly reduced mortality by 65–90% when administered intraperitoneally (i.p.) 1 h before Jo2 injection, a time when TRO40303 plasma concentrations reached their peak. TRO40303 (30 mg/kg, i.p.) was also able to reduce mortality by 30–50% when administered 1 h postlethal Jo2 intoxication. These results suggest that TRO40303 could be a promising new therapy for the treatment or prevention of hepatitis.

show abstract

Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial

Cited by 32 publications

References 30 publications

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria

TRO40303, a mitochondrial‐targeted cytoprotective compound, provides protection in hepatitis models

Contact Info

Product

Resources

About