Therapeutic applications of thyroid hormone analogues

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Pleasecitethisarticleinpressas:VisserWE.Therapeuticapplicationsofthyroidhormoneanalogues.AnnEndocrinol(Paris)(2020),

https://doi.org/10.1016/j.ando.2020.03.004

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ANDO-1163; No.ofPages3

Annalesd’Endocrinologiexxx(2020)xxx–xxx

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2020

:

Heart

and

Hormones

Therapeutic

applications

of

thyroid

hormone

analogues

W.E.

Visser

DepartmentofInternalMedicine,RotterdamThyroidCentre,ErasmusMedicalCentre,Rotterdam,Netherlands

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Keywords:

Thyroidhormoneanalogues Triac

MCT8

Resistancetothyroidhormone TR␤

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Cellularthyroidhormonehomeostasisrequiresadequatefunctionof:(1)thyroidhormonetransporter proteinsattheplasmamembrane,(2)deiodinatingenzymesand(3)nuclearthyroidhormonereceptors (TRs).Defectsinanyoftheseprocessesgiverisetodistinctdiseaseentities,collectivelycalledthyroid hormonesignalingdisorders.Thyroidhormoneanaloguesholdtherapeuticpotentialinthyroidhormone signalingdisordersbybypassingdefectivetransportersorbindingtomutantTRs.Thisreviewwillfocus ontheapplicationofanaloguesinthyroidhormonesignalingdisorders,particularlymonocarboxylate transporter(MCT)8deﬁciency,andresistancetothyroidhormoneduetomutationsinTR␤(RTH␤)

1. Introduction

Thyroid hormone is crucial for normal development and metabolismofalltissues.Cellularthyroidhormonehomeostasis requiresadequatefunctionof[1]thyroidhormonetransporter pro-teinsattheplasmamembrane,[2]deiodinatingenzymesand[3]

nuclearthyroidhormonereceptors(TRs).Defectsinanyofthese processesgiverisetodistinctdiseaseentities,collectivelycalled thyroidhormonesignalingdisorders.Thyroidhormoneanalogues holdtherapeuticpotentialinthyroidhormonesignalingdisorders bybypassingdefectivetransportersorbindingtomutantTRs.The useofthyroidhormoneanalogueshasalsobeenexploredforother diseases.Inthepast,itsroleinTSHsuppressionassubstituteor adjuncttolevothyroxinetherapyinthyroidcancerhasbeen inves-tigated[1].Inrecentyears,thyroidhormoneanalogueshavebeen appliedinmorecommondiseasessuchasnon-alcoholic steato-hepatitis[2]oraslipid-loweringtreatment[3].Thisshortreview willfocusontheapplicationofanaloguesinthyroidhormone sig-nalingdisorders,particularlymonocarboxylatetransporter(MCT8) deﬁciency.

2. MCT8deﬁciency

MCT8 is a speciﬁc thyroid hormone transporter that is cru-cialfortransportoftri-iodothyronine(T3)andthyroxine(T4)in severaltissues,includingthebrain[4–7].Mutationsinthegene encoding MCT8(SLC16A2onchromosome Xq13.2)causeMCT8 deﬁciency, alsoknown asthe Allan-Herndon-Dudley syndrome

E-mailaddress:Ewe.visser@erasmusmc.nl

(AHDS),adebilitatingdisorderwithanestimatedprevalenceof1 in70,000maleindividuals[8].MCT8deficiencyischaracterized byprofoundintellectualandmotordisabilityduetoahypothyroid stateinthebrain.Endocrineabnormalitiesassociatemarked ele-vationofserumT3concentrationswithlowtolow-normal(F)T4 concentrationsandnormalTSHconcentrations.TheincreasedT3 concentrationsresultinathyrotoxic stateinmany organs, con-tributingtoadeteriorationofbodyweightforageovertime,muscle wastingandtachycardia[8].ThelowT4concentrationsmeasured inpatientswithMCT8deficiencyintheneonatalscreening indi-cates the potential to diagnose MCT8 deficiency in newborns, perhapswithamodificationofthecurrentneonatalscreening strat-egy.

The phenotype is due to defective thyroid hormone trans-portbymutantMCT8.MCT8-dependenttissues(e.g.brain)arein ahypothyroidstate,whileMCT8-independenttissues(e.g.liver, muscle,heart)normallysensetheelevatedserumT3 concentra-tions.Theclinicalfeaturesarethenetresultofhypothyroidand hyperthyroidtissues.

Apart from empirical symptomatic treatment, a number of therapeuticoptionshavebeenexplored.Thyroxinereplacement therapyisnoteffectiveinnormalizingFT4levelsandratherfurther worsenstheincreasedserumT3concentrations,probablydueto immediateconversionofT4toT3[9].Acombinationofthe antithy-roiddrugPTUandthyroxinehasbeenshowntonormalizeserumT3 andT4concentrationsand,consequently,alleviatingsomeclinical featuresduetothethyrotoxicity.Thoseapproachesareunlikelyto improveneurodevelopment,asthyroxineisnotexpectedtoenter thebraingivenitsMCT8-dependentuptake.Also,asPTUhasan unfavorablesafetyproﬁle,therisk-beneﬁtratioshouldbetaken intoaccountwhencounselingparents.

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2 W.E.Visser/Annalesd’Endocrinologiexxx(2020)xxx–xxx Effectivetherapyshouldbothnormalizetoxicthyroidhormone

effectsinperipheraltissuesandimprovethehypothyroidstatein brain.Therefore,analoguesthatmimicT3actionbutrelyonother transportersthanMCT8forcellularentryaresuitedtoreverseor preventtheneurologicalphenotypeinsuchpatients.Also,T3 ana-loguesexpectedlynegativelyregulateTSHconcentrations,thereby reducingendogenousthyroidhormoneconcentrations.

Diiodothyropropionicacid(DITPA)andtriiodothyroaceticacid (Triac)aretwodifferentthyroidhormoneanaloguesthathavebeen investigatedinMCT8deﬁciency.AfterbeneﬁcialeffectsinMct8KO micewerenoted,DITPAhasreportedlybeenappliedin4patients

[10,11].SerumT3andsex-hormonebindingglobulin(SHBG)

con-centrationsimprovedinallpatients,althoughnoconsistenteffect onbodyweightwasobserved.Theabsenceofbeneﬁcialeffectson theneurologicalphenotypecanbeexplainedbydifferent possi-bilitiesincludingtheirreversibilityofbraindamage,agebeyond therapeuticwindoworinsufﬁcientaccesstothebrainwiththeused doses.

Triacwasabletonormalizetheabnormalbraindevelopment inMct8/Oatp1c1double KOmice,themousemodelmost accu-ratelyreflectinghumanMCT8deficiency[12].AbnormalPurkinje celldevelopmentinMct8/Oatp1c1doubleKOwasimprovedwith alowdoseofTriacandfullyrestoredwithahighdoseofTriac.Also, TriacwasshowntoenterfibroblastsofMCT8deficientpatientsto asimilarextentascellsfromunaffectedindividuals[13].

Basedonthesepreclinicalstudies,an internationaltrialwas startedtoinvestigatetheeffectsofTriac inpatientswithMCT8 deﬁciency,theresultsofwhichhavebeenreportedrecently[8].In total,46patients(medianage7.1years[range0.8–66.8])received Triacfor12monthsand asubsetofthepatientswereincluded ina long-termtreatment-extensionperiod. After12 months of Triactreatment,serumT3concentrations(primaryendpoint)were largelyreducedinallpatients.

In patientswho completed the 12-monthtreatment period, therewasasignificantmeanincreaseinweightforage.In addi-tion,systolicbloodpressureandrestingheartratedecreasedand alsothehighnumberofprematureatrialcontractionswaslargely reduced.Differentmarkersforthyroidhormoneactionintissues (e.g.creatine kinase,creatine, SHBG)improved. Triac waswell toleratedwithonlymildandtransientsymptomsofperspiration andirritability.Together,Triacwassafeandeffectively normal-izedtheserumT3concentrationsinpaediatricandadultpatients withMCT8 deficiency with sustainable improvements in clini-callyrelevant outcomesincluding body weight, heart rate and blood pressure. Being severelyunderweight and cardiovascular dysfunctionareimportantclinicalsequelaeofchronicperipheral thyrotoxicosis,causingsignificantmorbidityandmortalityinMCT8 deficiency,ameliorationofthethyrotoxicosis underTriac treat-mentbenefitspatientswithMCT8deficiencyirrespectiveoftheir age.

Anotherphase 2 clinical trial will investigate the effects of Triaconneurodevelopment,withtreatmentbeingstartedatavery youngage(NCT02396459).ThefuturewillrevealifTriachasthe potentialtomodulatetheneurodevelopmentinMCT8deﬁciency.

3. ResistancetothyroidhormoneduetomutationsinTR␤

(RTH␤)

Themaineffectsofthyroidhormoneareexertedthrough bind-ingofT3toitsnuclearreceptor(thyroidhormonereceptor,TR), whichfunctionsasa ligand-dependenttranscription factor.The mainT3bindingreceptorisoformsareTR␣1andTR␤1and2,which differintheirtissuedistribution[14].

HeterozygousmutationsofTR␤arethemostcommongenetic cause of RTH␤ and have a prevalenceof – 1:50,000 [15]. The

endocrinehallmarkofRTH␤areelevatedserum(free)T4andT3 concentrationsaccompaniedbynon-suppressedorelevatedserum TSHconcentrations.TheclinicalfeaturesofRTH␤comprisea com-binationofhypothyroidandthyrotoxicsymptoms,resultingfrom the tissue-speciﬁc distribution of theTR isoforms. T3 action is reducedinTR␤-expressingtissues(e.g.pituitaryandliver)[16,17]. Incontrast,TR␣-expressingtissues(e.g.heartandbrain)normally sensethehighserumthyroidhormoneconcentrationsandmay resultintachycardia,hyperactivity,anxietyandlearning

disabili-ties[16,17].ThereisawideclinicalspectruminRTH␤,rangingfrom

asymptomaticindividualswithabnormalthyroidfunctionsteststo patientswithaseveremotorandintellectualdisability.Therefore, theneedfortreatmentisassessedonanindividualbasis[15].Inthe majorityofpatientswhosufferfromtachycardiaandpalpitations, symptomatictreatmentwithbeta-blockersissufﬁcienttoalleviate thosesymptoms.

In patientsthat do notrespondtothose treatment possibil-ities, an ideal treatment should selectively increase T3 action in TR␤-expressing tissues while maintaining euthyroidism in TR␣-expressingtissues.TriacpreferentiallyactsthroughtheTR␤ isoform[19–21].Importantly,Triacexhibitsahigherafﬁnitythan T3forseveralTR_␤mutants[19–21].

Theseinvitroobservationsareinlinewithcasereportsandcase seriesinpatientswithRTH␤(foranoverview,see[22]).Dependent onthemutation,Triachasthepotentialtoinhibit TSH produc-tionand secretion,resulting ina reduction in serum (F)T4and (F)T3concentrations.Asaconsequence,a(partial)alleviationofthe thyrotoxicsymptomsincludingtachycardia,excessiveperspiration andbehavioralproblemscanbeexpected.Theputativenegative effects of therelatively highdosesTriac in theTR␣-expressing tissues,includingthebone,aredifﬁculttoevaluatebasedonthe availableliterature.

Clinicaltrialsandlong-termfollow-upstudiesarerequiredto describe thepositive and adverse effects of Triac at the tissue levelinRTH_␤inmoredetail.Itwouldbeofclinicalrelevanceto documenttheeffectsofTriacinRTH␤patientsusingestablished treatmentprotocolsandwell-deﬁnedoutcomemeasures.

4. Perspectives

Ever since the report of Triac in 1953 [23], the ﬁeld has activelydevelopedandtestedotherthyroidhormoneanalogues. Thepotentialapplicationofsuchanaloguesvariesfromselected rarethyroid hormone signalingdisorders (e.g.RTH␤and MCT8 deﬁciency) to more common diseases (e.g. multiple sclerosis, hypercholesterolemiaandNASH)[2,8,24–27].Rationaldesignof thyroidhormone analogueswithappropriatepreclinicalstudies shouldpavethewayforclinicaltrialsinpopulationswithrareand commondisorders.

Funding

ThisresearchwasfundedbytheNetherlandsOrganisationfor HealthResearchandDevelopment(projectnumber113303005;to WEV),theShermanFoundation(toWEV).

Disclosureofinterest

TheErasmusMedicalCentre(Rotterdam,Netherlands),which employsWEV,mightreceiveroyaltiesfromRareThyroid Thera-peutics(themanufacturerofTriac)inthefuture,dependentonany futurecommercialisation.Theauthordeclareshehasnocompeting interest.

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