Metabolic Matters (Issue 12)

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A focus on: OTC Deficiency Metabolic Matters Y O U R Q U A R T E R L Y M S U K M A G A Z I N E A U G U S T 2 0 2 3 A U G U S T 2 0 2 3 Ava'sLifeWithOTC Deficiency,Page5-6 AnintroductiontoClinical Trialsthroughthelensof OTCDeficiency Findoutaboutupcoming projectsfromMSUKand changestoourcommunity

CONTENTS

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Clinicaltrials:AfocusonOTCDeficiency

OrnithineTranscarbamylaseDeficiency–AllaboutOTCDeficiency

Ava'sLifewithOTCDeficiency

TheFocusonOTCDeficiencyExplained

TheScience-What'sgoingonandwhydoIneedtoknowaboutit?

ArcturusTherapeutics

BloomsburyGeneticTherapies

iECURE

AnOverview-Toplineinformation

Currentworkin OTCDeficiency.

DoYouFeelResearchReady?-OurupcomingeModule

ShareYourExperience-HyperammonaemiaSurvey&DietDirectory

NewandImproved-TheCoffeeLounge&MetabolicConnect

SupportUstoSupportOthers-2024LondonMarathon

GetinTouch&Wordsearch

Clinical Trials: A focus on OTC Deficiency

Allnewtreatmentsandtherapiesmustgothrough rigorous testing which is in line with ethical standardsandregulations.Clinicaltrialsareaform ofresearchwhichtestsatreatmentortherapyand evaluatesitslong-termsafetyanddetermineshow effectiveitisbymeasuringtheimpactondifferent health-relatedoutcomes.

There comes a point where clinical trails may rely onpeopleparticipatinginthemtoprogress.

Currently there are multiple clinical trials for OTC deficiency in development or on-going. It can be hard to keep all the different companies and techniquesstraight!

We put together this bumper edition of Metabolic Matters about clinical trials and current work on OTC, not to convince you to take part in anything, but to ensure you understand all the potential options, what they actually mean, and what the futureofOTCdeficiencycaremaylooklike.

Ornithine Transcarbamylase Deficiency

AnintroductiontoOrnithineTranscarbamylase Deficiency,arareUreaCycleDisorder.

AlsoknownasOTC,OrnithineTranscarbamylaseDeficiencyisarareinherited metabolicconditionnamedfortheenzymethatpeoplewithOTCaremissing.

Butwhatdoesthatmean?

Manyfoodscontainprotein.Youmayimmediately thinkofthemoreobviousfoodslikechicken,but proteincanalsobepresentinotherfoods,likesweets andvegetables.Thebodyneedsproteinforgrowth andrepair.Manypeopleeatmoreproteinthanthey needandsothebodyremovestheexcessprotein.

Unusedproteinfirstgetsconvertedintoatoxicchemicalcalledammonia.Thischemical cancausedamagetothebodyandbrainifit’snotremovedandisallowedtobuildup. Usually,ourbodiesremovetheammoniathroughaprocessknownas:

TheUreaCycle

TheUreaCycletakesplaceintheliver.Itconverts ammoniatoanon-toxicchemicalcalledurea.Several stepshavetotakeplacewithinthecycletoachieve thisandeachstepneedsanenzyme(likechemical scissors)forittowork.Ureaisthenremovedfromthe bodybythekidneys,beforeit'sexcretedasurine.

InOTCdeficiency,thebodylackstheenzymeornithine transcarbamylase.Thismeanstheprocessabove cannothappen.Thelivercannotconvertthewaste proteinintoureaasfastasitusuallywould.Thiscan leadtohighlevelsofammonia.

Thisbuildupinammoniameanssomebabiescan becomeillinthefirstfewdaysoflife,whilstsomemay bediagnosedlateraschildren.Forboth,theeffectsof highammonia,knownashyperammonaemia,can quicklybecomelife-threateningifuntreated.

OTCisestimatedtooccurbetween1in56,500to1in77,000people.

ConditionSpotlight Page3

DiagnosisandManagement

CurrentlyOTCdeficiencyissuspectedinsomeonewithhighammonialevels,whichcanbe pickedupthroughabloodtest.Diagnosisisthenconfirmedbyfindingamutationinthe OTCgene.

Babiesmaypresentwith:

Poorfeeding

Floppiness

Excessivesleepiness

Rapidbreathing

Dehydration

Seizures

Childrenmaypresentwith:

Seizures

Learningdifficulties

Repeatedepisodesof vomitingwhichmay leadto:

Sleepinessandcoma

Developmentaldelays

OTCdeficiencyismanagedwithaproteinrestricteddiet,regularfeeding,andmedications andsupplements.It’simportanttogettheproteinbalanceright!Toolittleandthere’snot enoughtogrow,toomuchandwasteproteinwillcausehighammonialevels.Somemay needafeedingtubetohelpwiththis,ormightconsideralivertransplantifmanagement isn'tsufficienct.

TheGeneticsofOTCDeficiency

OTCdeficiencyiscausedbyamissingorfaulty enzyme.Itisourgenesthatcodeforthingslike enzymesinourbody,andwegetourgenesfrom ourparents.

Hundredsofgenesmakeupachromosome,and eachhumanhas23pairsofchromosomes. FemaleshavetwoXchromosomeswhilstmales haveonXandoneY.

TheOTCgeneisfoundintheXchromosome.As malesonlyhaveoneXchromosome,allmales withOTCdeficiencyareexpectedtohave problems.

Femaleswiththemutationmayneverget problemsasthebodyonlyneedsoneworking copyoftheXchromosome.

ConditionSpotlight Page4
ThisinformationiseditedfromtheTEMPLEGuideswhichhavebeenadaptedbytheDietitiansGroupoftheBritishInheritedMetabolic DiseaseGroup(BIMDG)andisbasedontheoriginalTEMPLEwrittenbyBurgardandWendel TheTEMPLEGuidesaresupportedbyNutricia

Ava's Life with OTC Deficiency

Avasharedherstorywithustoshowwhatlifewith OTCdeficiencyandalivertransplantcanlooklike.

nosedwithOTCdeficiencyateightmonths multiplehospitaladmissions,shehada .Despiteherdietandnutritionbeing cian,Avastillregularlyneededan ammonialevelsfromrising

AttheageoffiveAvawasdeemedtoounstable andreceivedalivertransplant.Shefaced18 difficultmonthsofsevererejectionbeforeshevery slowlybegantoimprove.Gradually,andwiththe helpofprofessionals,shelearnedtoeat; somethingwhichshehadneverdonebefore.Four yearslaterhergastrostomywasremoved.

Avahasalwayslovedswimming,buthercondition andgastrostomymadeitdifficult.Withtheremoval ofhergastrostomyandslowlybuildingupherstrength andstaminaafterhertransplant,Avacannowfullyenjoyswimming.

Notonlydoessheswimregularlywithherlocalclub,butshehasalso competedattheBritishTransplantGamesandrepresentedGreatBritainat theWorldTransplantGames!AtherfirstWorldTransplantGamesin2019 shewonfivegoldmedalsandsetfourworldrecordsinheragecategory!

2023World

,setanew

A
T
w
CommunityStory
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‘I am so proud of Ava. Despite everything she has been through she always has a smile on her face and never ever complained at missing out on the normal childhood events growing up. Even when she was well, she still often had to miss out on activities due to the risk of getting childhood illnessesthatcouldhavehadseriousconsequencesforAva. Being part of the Leeds Transplant team and now Great Britain has helped build Ava’s confidence, allowed her to makelifelongfriendsandnotfeeldifferent’.

Caroline,Ava'sMum

WeaskedAvaandherMumsomequestionsfollowingtheirrecenttriptoAustralia forthe2023WorldTransplantGames,Ava'smumletusknowthefollowing:

Whatdoyoufeelisyourbiggest achievementsofar?

"Beingabletorepresenthercountry,and themedalsandworldrecords.Butalso justthesimplethingslikewhenshe’s eatingwhatshewantsandlookshealthy andsmiling"

Ifyoucoulddescribetheeventinone word,whatwoulditbe?Andwhy?

"TherearesomanybutIreallyfeel emotionalandproud(ifIcouldhave2) whenIthinkbacktohowAvawaswhen shewasfirstdiagnosed,endlesshospital stays,emergencyregimes,havingtobe theexperteveninthehospitalwhenIwas reallyscared.Tothenwatchherswimher heartoutandstandonthepodium makesmesoemotionalandproud.The atmosphereandcamaraderieof everyonetherewhohasfacedlife threateningconditionsallenjoying themselvesistrulyhumbling."

Caroline,isthereanythingyou’dliketo sharewithotherparentswhomaybe worriedabouttheirchild’sdiagnosis and/ortheorgantransplantprocedure?

"Itfeelslikeyouaregamblingwiththe mostpreciousthingintheworld.Doyou riskstayingasyouare,ortryforsomething better.Weareextremelylucky.Butitisnot aneasyroad.Thefirst18monthsfelthard andImanytimeswonderedifIhadmade therightdecisionbutthenslowlythings startedtoimprove Youneverfullyrelax, butIwouldn’thavedoneifshehadn’thad hadthetransplanteither ButIdobelieve Avahasabetterqualityoflifenowthan shewouldhavehad.Shewasfortunateto getagoodliverandwealwaysthankher donorfamily,withoutthemnoneofthis wouldbepossible Theymadesucha difficultdecisionattheworsttimefor them Buthope,knowingAvaismakingthe mostofeveryopportunityandlivinglifeto thefullwillbringthemsomehappinessin theirloss."

CommunityStory Page6
AvaalreadyhashersightsonGermany2025WorldTransplantGames.

Explained:TheFocus

FindoutmoreaboutthefocusonOTCDeficiency andthesciencebehindsomeoftheclinicaltrials.

ThereisafocusonOTCdeficiencywithintheclinicaltriallandscapeatthemoment.Many researchersandcompaniesareshowinginterestinthisrarecondition,withactiveand upcomingclinicaltrialseithertostudynewtreatmentsorbetterunderstandthecause andeffectsofOTC.

Currently,OTCismanagedthroughdietandmedication,butthisdoesn'taddresstheroot causeoftheissues.Livertransplantistheonlycureatthistime,andwhilstthiscanbean incredibleimprovementformany,itcancomewithrisksandcansometimesbeseenas resolvingonethingthatneedsmanagingbutreplacingitwithanother.Anyonewho's undergoneorgantransplantneedstotakedrugstosuppresstheirownimmunesystem andreducetherisksoftheorganbeingrejectedbythebody.Whereitisanoption,the decisiontogoaheadwithalivertransplantisthereforeonethatneedscareful consideration.

ButwhyOTC?

There’snoclearlycitedreasonforthecurrentindustryfocusonOTCwe’re seeing.Thoughtherecouldbeafewofreasonsforthis:

DespiteUCDsbeingrare,thereisgoodunderstandingoftheureacycleitself. OTCisalsothemostcommonoftheUreaCycleDisorders. LiketheotherUCDs,treatmentisfocusedsolelyaroundpreventingthebuildupofammoniaandthesubsequenteffectsofthissoit’srelativelyeasyto testandprovethehowwellatreatmentworks,withclearmarkersand symptomsthatareeasilyidentifiedandmeasured.

Howandwheretheenzymesoftheureacyclearelocatedisvastly important,thissolelybeingintheliver.Alivertransplantthereforecanbe curative.Livertransplantationalthoughlargelypositiveisgenerally consideredforthosewithmoresevereillness.

Currenttreatmentsofdietandmedicationareburdensomeandcanbe trickytonavigateandmaintain.

Thesciencebehindnewtreatments

Aswementioned,OTCdeficiencygetsitsnamefromtheenzymethatismissingorfaulty. Ourgenes(DNA)providetheinstructionsformakingourenzymes.Clinicaltrialsarelooking atwaystodeliverthefullandcorrectinstructionsformakingthenecessaryenzymetowhere they'reneeded.Therearedifferentwaystodothis,eachwithitsownpositivesandpotential risks.Thefollowinginformationisonlyanintroductiontosomemethodsindevelopment.

the focus on OTC Deficiency Page7

AAV Gene Therapies

AAVstandsforadeno-associatedviruses

Thisisacommonformofgenetherapythatusesa naturallyoccurringvirustodelivertheinstructions usingDNA.Itcansoundabitscary,butoncetheDNAof thevirushasbeenswappedforthespecificDNAcode ofthemissingenzyme,it'snotreallyconsideredtobea virusanymore!Thismethoddoesn'tcreatepermanent changestosomeone'sgenes.Whencellsdivideand grow,thesenewcellsstillcontainthemissingor incorrectgene.Thiscanmakeitchallengingtousein newbornswithOTC,becauseasthebabyandtheir livergrowsthereplacementgenemaybelost.

Gene Editing

Geneeditingisanotherformofgenetherapy.Geneeditingessentiallydoes whatitsays,iteditssomeone'sgenes(DNA).Editingcanmeandeleting, modifying,orreplacing.Thiscreatesamorepermanentchange.ForOTC thehopeistoreplacethatfaultyormissingbitofcodefortheenzyme,so excessproteincanbesafelyremovedfromthebody.

TheCOVID-19jabwas anmRNAvaccine!

mRNA Therapy

Thisisnotagenetheapy

MessengerRNA(mRNA)therapydoesn’tinteractdirectlywithDNA.Thismeansitdoesn’t alterthegeneticcode.WhilstourDNAprovidestheinstructionsforproducingenzymes, mRNAworksasamessengerinthatproductionprocess.Itrelaystheinstructionsfromour genestothe“assemblyline”wheretheenzymesareproduced.mRNAisnotpermanentand isnaturallybrokendownbythebody.ThismeansmRNAtherapyneedstoberepeatedfor lastingbenefit,butitcanalsobepausedorstoppedifsideeffectsoccur.

WhydoIneedtoknowthis?

Therehavebeenlotsofupdatesaboutpotentialfutureclinicaltrialsand newdevelopmentsforOTCrecentlyandthesehavebeensharedasandwhen informationhasbecomeavailable.MetabolicSupportUKiscommittedtoempowering thoselivingwithIMDsandtheirfamiliesorcaregivers.Weprovideimpartialinformation aboutpossiblenewtreatmentsbutalsoacknowledgethatthesciencebehinditcanbe complicatedandeasilymisunderstood.

Wehopethatthedefinitionsabovehelpalittleaswecontinuethroughthenextcouple ofpageswhereweexploretheongoingworkofsomeofthecompanieswhohave upcomingplansforclinicaltrialsforOTC.Besuretoalwaysdiscussanypotentialrisks withyourconsultantortheleadinvestigatoroftheclinicaltrial,alongsidethepositives.

Healthy Gene Virus Viruscontaining healthygene Explained:TheScience Page8
Aformofgenetherapy

WhoisArcturusTherapeutics?

ArcturusTherapeuticsisararediseasesandvaccinescompany,withpeoplewhoare workinghardtobringlife-changingtherapiestoindividualswithraregeneticdiseases likeOTCdeficiency.Arcturusdevelopsmedicinesmadewithamoleculeknownas messengerRNA(mRNA).EachmRNAisuniquelydesignedtotreataspecificdisease.The mRNAisthenpackagedintoparticlestotransportthemRNAtothespecificareasinthe body.

WhatworkisArcturusTherapeuticsdoing?

ArcturusisconductingtwoclinicalstudiesinvolvingtheARCT-810investigational treatmentforpeoplelivingwithOTCdeficiency.Foranoverviewofthesestudies,please see“OurStudies”ontheLUNAR-OTCwebsite.

ThemRNAinARCT-810isdesignedtobeatemplateformakingOTCenzyme.Arcturus usesitslipidnanoparticletechnology(Figure1),calledLUNAR®,totransportthemRNAto thespecificareasintheliverthatmakeOTC

IndustryUpdates:Arcturus Page9
Figure1.ARCT-810,aninvestigationalmRNAmedicineforOTCdeficiency,putsmRNAinto alipidnanoparticletotransportmRNAtothelivertomakethefunctioningOTCenzyme
revisitpage8for areminderof mRNATherapy
ArcturusTherapeuticshasaclinical-stageprogram thataddressesthecauseofOTCdeficiency.

Thefirststudy,ARCT-810-02,isbeingconductedintheUnitedStatestoevaluatethe safetyandtolerabilityofsingledosesofARCT-810inadults18yearsandolderwith clinicallystableOTCdeficiency.ItwillalsomeasurethelevelsofARCT-810inthebody overtimeandwillexplorewhetherasingledoseofARCT-810cantemporarilyincrease OTCactivityinthebody.Thisstudyisnowfullyenrolled.

Thesecondstudy,ARCT-810-03,nowunderwayinthe UnitedKingdomandEurope,willevaluatethesafety andtolerabilityofsixdosesofARCT-810inadolescents andadults(12to65yearsold)withOTCdeficiency. Thisstudywillmeasurewhetherrepeateddosesof ARCT-810canincreaseOTCactivityandcanimprove ureacyclefunctioninthebody.

FormoreinformationaboutArcturus'sOTCprogram andthestudiesvisittheArcturusOTCstudywebsite and theirtrialonClinicalTrials.gov.

Thereisnocosttotakepartinthisclinicalstudy.Travelexpenses,suchastransportation andhotel,ifrequired,willbecovered.Youwillalsobereimbursedforothertravelexpenses thatarerelatedtoyourstudyvisitssuchasmeals,parking,andtaxifares.

Wherearethestudiestakingplace?

ParticipatingsitesintheUKincludeUniversityCollege LondonHospitals,GreatOrmondStreetHospitalfor Children,UniversityHospitalsBirmingham,andSalford RoyalHospital.

WherecanIgetmoreinformation?

IfyouwouldlikemoreinformationabouttheARCT-81003study,youcanclickheretovisitthestudysite,and clickonthebluebutton,“I’minterested,”intheupper rightcorner.

Tolerabilityisa measureofhow muchpeople arewillingor abletoputup withany unpleasantside effects.
IndustryUpdates:Arcturus Page10
Arcturus'sWebsite Arcturus'sStudySite

BloomsburyGeneticTherapieshasaprogramindevelopment forOTCdeficiency,alongsideothermetabolicconditions.

WhoisBloomsburyGeneticTherapies?

Bloomsburyisaclinical-stagebiotechnologycompanydevelopingpotentiallycurative treatmentsforpatientssufferingfromrareneurologicalandmetabolicdiseasesbasedon clinicallyprovengenetherapytechnologies.IncorporatedinAugust2021andlaunchedin October2022,BloomsburyisaUK-basedspin-outfromUniversityCollegeLondon(UCL).

Bloomsbury'sfouracademicfoundersfromUCLcombineworld-leadingclinicalinsights andpreclinicaldevelopmentexpertiseanditisbuildingateamofindustryleadersand subjectmatterexpertswithextensiveexperienceindevelopingandregisteringgene therapiesandrarediseasetreatments

WhatworkisBloomsburyGeneticTherapiesdoing?

BGT-OTCDisaliver-targetedAAVgenetherapy designedtoprovideapotentiallycurativesolutionto OTCDpatientsfollowingaone-timeintravenous injection.Theapproachistodeliverafunctioning copyoftheOTCgenetothecellsintheliverofOTCD patientsbyusingacertainharmlessvirustypecalled AAVasadeliverymechanism.Oncethevirushas delivereditsgeneticcargototheliver,normalurea cyclefunctionwouldberestored,andpatients wouldn’tneedtocontroltheirdietortotakeammonia scavengersanymore.Thisbenefitwouldbeachieved followingasingleinjection,andtheeffectmaybe sustainedformanyyears,ifnotdecades.This approachhasbeensuccessfullypioneeredinother rarediseasessuchasinhaemophilia,wheregene therapytreatmentswithpotentially curativeeffect haverecentlybeenapproved,includingintheUK.

BGT-OTCDwasinitiallydevelopedbyProfIanAlexander andAssociateProfLeszekLisowskiofChildren’sMedical ResearchInstitute(CMRI)inWestmead,Australia,in collaborationwithProfPaulGissenfromUCL.

IndustryUpdates:Bloomsbury Page11
revisitpage8for areminderof AAVGeneTherapies Viruscontaining theOTCgene

BGT-OTCDwillbeevaluatedinaPhase1/2clinicaltrialcalledHORACE (HaltingOrnithinetranscarbamylasedeficiencywithRecombinant AAVinChildrEn).

Aphase1/2clinicaltriallikethishastwoparts.Thefirstpartusually teststhesafetyoftheinvestigationaltreatment,givenatincreasing dosestopeoplewiththerelevantcondition.Inthesecondpart,adose fromthefirstpartisselectedandthetreatmentisgivenatthatdoseto abiggergroupofpeopletoconfirmitssafetyandfurtherstudyits effectiveness(knownasefficacy).

ThetrialisexpectedtobegininSeptember2023andwillrecruitabout sixpeoplelivingwithOTCdeficiencyagedbetween6and16inthefirst partandabout6agedbetween0and16inthesecondpart.

BloomsburyisprovidingfinancialsupporttoUCLforthetrial.Thereare nocoststofamiliesfortheirchildtoparticipateinthetrial.

Bloomsbury'sWebsite

Wherearethestudiestakingplace?

TheHORACEtrialwillbesponsoredbyUCLunderthe supervisionoftheprimaryinvestigatorDrAnupam Chakrapani,consultantinMetabolicMedicineatthe GreatOrmondStreetHospital(GOSH),wherethetrialwill takeplace.ThreeotherUKhospitalswillcollaboratewith GOSH:EvelinaLondonChildren’sHospital,Royal ManchesterChildren’sHospitalandBirmingham Children’sHospital.

WherecanIgetmoreinformation?

MoreinformationaboutHORACEisavailablehere.

FollowingHORACE,BloomsburyintendstoevaluateBGTOTCDinlargerclinicaltrialsinbothchildrenandadult withOTCD,andincountriesbeyondtheUK,asrequired foritsultimateapprovalasatreatmentoption.

IndustryUpdates:Bloomsbury Page12
ClinicalTrialsSite

IECUREisactivelyworkingtoprogresstowardsaclinicalstudy fortheirnewgeneeditingapproachinthecomingmonths.

WhoisiECURE?

iECUREisabiotechcompanyresearchinggeneeditingtherapiesforthetreatmentofrare andlife-threateningdisordersinchildren.Specifically,theyfocusongeneediting therapiesthataddressraregeneticdisordersinvolvingtheliverincludingOTCdeficiency. ThetechnologyandsciencebehindiECURE'sgeneeditingtherapiescomesfroma collaborationwiththeUniversityofPennsylvania’sGeneTherapyProgram(GTP)ledbyDr. JamesWilson.Theirmostadvancedgeneeditingprogramisfocusedonapotential treatmentforneonatalonsetofOTCdeficiency.

iECUREhasbuiltastrongteamofexpertstoleadtheir OTCdevelopmentprogram,mostnotably,Dr.George Diaz[pictured],theirtherapeuticarealeadforurea cycledisorders.GeorgejoinediECUREafterservingas theleaderoftheProgramforInheritedMetabolic DiseasesattheIcahnSchoolofMedicineatMount SinaiinNewYorkCity.Georgehasbeentreating newbornsandadultswithinheritedmetabolic disordersformanyyearsandhasestablisheda reputationasago-toexpertinureacycledisorders includingOTC.Georgehasworkedextensivelyonthe clinicaldevelopmentandresearchofmanydifferent potentialtherapiesfortreatingureacycledisorders andwasdrawntoiECUREbasedonthepotential promiseofthegeneeditingtechnology.

WhatworkisiECUREdoing?

Geneeditingisaninvestigationaltechnologythattargetstheunderlyingcauseofa diseaseatthecellularlevel.iECURE’sapproachintroducesafull,healthycopyofagene responsibleforthedisorderinaveryprecisespotintheDNAoftargetedcellstorestore theabilityofthesecellstoproducethemissingornithinetranscarbamylaseenzymeand regainnormalfunction.

TheirhopeisthattheinsertionofthehealthyOTCgenewillallownewbornswithneonatal onsetOTCdeficiencytomakehealthycopiesoftheOTCenzyme,resolvingthebroken metabolicpathwaythatcausesOTCdeficiency.

IndustryUpdates:iECURE Page13
revisitpage8for areminderof GeneEditing

iECUREusesa“knock-in”geneeditingapproachthatintroducesahealthy copyofthetargetgeneintoaperson’sDNA.Thisisdifferentfromother geneeditingapproachessuchasgene“knock-out”and“baseediting” thatseektomodifytheexistinggenesinaperson’sDNA.Genetherapy differsfromgeneeditinginthatanewfunctionalgeneisintroduced intoaperson’scellsbuttheperson’sDNAremainsthesame.

Wherearethestudiestakingplace?

iECUREisactivelyworkingtowardsaclinicalstudyfor neonatalonsetOTCdeficiencyinthecomingmonths. Thisstudywouldbeconductedinanumberofcountries, includingtheUK,afterthecompanyhasreceivedthe requiredregulatoryapprovalstoproceed.

WherecanIgetmoreinformation?

FormoreinformationaboutiECURE,pleasevisit

iECURE'sWebsite IndustryUpdates:iECURE Page14
http://www.iecure.com.

An Overiview

We'vecoveredalotofinformationintheprevious pages,here'sanoverviewofeachfeaturedcompany.

2clinicalstudiesusinganmRNA therapycalledARCT-810

Study1(ARCT-810-02)exploresasingle doseforage18+withstableOTC deficiencyintheUSA

Study2(ARCT-810-03)explores repeateddosesinages12-65withOTC deficiency.

UKstudysitesatUCL,GOSH, Birmingham,andSalford

BGT-OTCDisapotentiallycurative, singledoseliver-targetedAAVgene therapy

TreatmentisexploredintheUKinthe HORACEtrialrecruiting12patients betweenages0-16,expectedtostartin September

TrialtakingplaceatGOSH,in collaborationwithLondon,Manchester, andBirminghamcentres.

Theirinvestigationaltherapyusesa geneeditingtechnique.

Insertedcopyofthehealthygenehopes toallownewbornstoproducehealthy copiesoftheOTCenzyme. Clinicalstudydetailsnotyetavailable butexpectedinthecomingmonths.

Studysitesacrossmultiplecountries, includingtheUK.

This is just the information we have so far. More work is being done by others such as Ultragenyx and Moderna, and we'll share this as soon as it's available to us.

Wehopethisinformationhasbeenhelpfulandprovidesabalanced overviewofthefutureworkinOTC.Wehopethisempowersyouto understandthedifferenttypesofinvestigationaltherapiesoutthere andgivesabriefinsightintoeachtrial.Althoughclinicaltrialsmustgain approvalsandfollowstrictregulationsandprocessestoensuresafety,all clinicaltrialscarrysomedegreeofrisk.Therefore,ifyoudohaveaninterest inparticipatinginaclinicaltrialitisimportantyougatherallinformation available.Youcandiscussthiswithyourconsultantortheleadinvestigator ofatrialwho’llbehappytoprovidemoreinformationandhelpyoumake aninformeddecisionwithoutcommittingtoparticipating.

IndustryUpdates Page15

Do you feel Research ready?

Sowhatelsearewedoingtosupport? AnintroductiontoourupcomingeModule.

Didyouknowtherearefivestagesto clinicaltrialsandtesting?Orthatthis testingisjustoneofsixstagesofthe productionanddevelopmentofmedicine?

WearedevelopingouronlineAccessto Medicinescourse,startingwithour MedicineDevelopmentLifecyclemodule. Thisfirstmoduleisdesignedtogiveyouan overviewandunderstandingofthe medicinesdevelopmentprocessfromprediscoverytomanufacturingand monitoring.

Theworldofrareconditionscanbefullof jargonandacademicwriting.Itcanbe difficulttonotonlyfindtheinformationyou need,butalsodifficulttounderstandit.Yet despitethispotentialbarrier,our communityareoftenacknowledgedasthe expertsintheirconditions.

Wewanttobuildonthis,empoweringour communitytobeabletomakeinformed

decisionsabouttheir careandengagement inclinicaltrials.There comesapointinthedevelopmentlifecycle ofanewmedicineortreatmentwhereit’s essentialtohavepeopletakepartinthe testingtomoveforward.Thedecisionto,or nottotakepartinaclinicaltrialcanbe complicatedforfamiliesandpeopleliving withrareconditionsforawholerangeof reasons.

Therecanbefearofpotentialrisks,worries aboutupsettinga“stable”condition,or concernsaroundreceivingaplacebo.Not tomentionadditionallogistics,liketravel, expenses,andsimplytime.

Gainingabetterunderstandingofthese processeshelpsremovethefearofthe unknown.Youcanenterconversations fullyinformed,armedwiththequestions thatmattertoyou.Itputsthepowerfirmly inyourhands,andwe’reexcitedto introducethiswork.

GetInvolved Page16
Wewouldlovetoseeyousignup oncetheeModulegoeslive. Keepaneyeoutonourwebsiteand socialmediatokeepuptodatewith newsaboutthisandotherprojects!

Share your experience

Learnabouttheworkwe'redoingwithhyperammonaemia andspecialiseddietsandhowyoucanshareyourvoice.

Our Hyperammonaemia Survey

Highammonialevels,knownas hyperammonaemia,isoftentheway peoplewithUreaCycleDisorderslikeOTC gettheirfirstsuspecteddiagnosis.

Theconditionsarenotscreenedforin NewbornScreening,andwiththecurrent timeframesitwouldn’talwayshelpif theywere.NewbornscreeningintheUK generallytakesplacearound5-8days afterbirth,butammoniacanspiketo increasinglydangerouslevelsbeginning frombirth.

Theeffectsofhighammoniacanquickly becomelife-threateningifuntreated.It canalsoleadtodamagetothebrain, causinglearningdifficultiesor developmentaldelays.Soitisnosurprise wehaveheardfrommembersofourUCD communityhowimportant hyperammonaemiaawarenessisto themandtheirfamilies.

Diet Directory

We’rekeentoheartheexperiencesof anyoneaffectedbyhyperammonaemia inourcurrentsurvey.Hyperammonaemia doesn’tonlyaffectpeoplelivingwithUrea CycleDisorders.Itcanalsoimpactpeople livingwithotherconditions,suchas OrganicAcidemiasandFattyAcid Oxidationdisorders.

Wewillusetheinformationprovidedfrom thesurveytohelpourunderstandingof experiencesfacedbythoseaffectedby IMDsandtheirfamilies,asarouteto diagnosisandwhenaccessing emergencycareservicesfor hyperammonaemia.Throughthis understandingwecanidentifygapsin awarenessandmoveforwardtoaddress theseissues.

clickheretotakepart

We’recurrentlyworkingonthedevelopmentofanewsectionofourresourcehubthatwill befocusedonspecialiseddiets.Thiswillincorporateanyupcomingrelevanteventsinthis area,aswellaslinkstoresources,signpoststousefulsites,andhelpfulhintsandtipsthat areprovidedbythosewithexperienceofIMDs,eitherinaprofessionalcapacityorfromour wonderfulcommunity.

Thisisacollaborativeeffortandsowewouldlovetohearfromyouifyouhaveanyideasor suggestionsaboutwhatyouwouldliketosee!Emailusathelen@metabolicsupportuk.org

TeamSpotlight Page17

New and Improved

We'verevampedsomeofourolderprogrammes tohelppeopleconnectandaccesssupport.

Changes to the coffee Lounge Metabolic Connect Has returned

Wearecurrentlyrunningatrialexpansion ofourcoffeeloungesessionsto incorporatethemedsessions.Theseare informalplacestoshareexperiences, gatherinformation,andgainfirst-hand knowledgefromotherslivingwithIMDs andtheirfamiliesonspecifictopicsand themes.

Thismonth’sthemeis‘Traveland Holidays’.

Weencourageyoutojoineitherofour themedsessionsifyouoramemberof yourfamilyhaveanIMDandhave recentlybeenonholidayorregularly travel,orifyouarelookingtogoabroad andarelookingforalittleguidanceor support.

Bothourthemedandgeneralchat sessions,whichhavenotheme,are approximately1hourlongandtakeplace onlineusingZoom.

AugustDates

GeneralChat:

Wednesday2ndAugust3pm-4pm

Wednesday16thAugust3pm–4pm

We’repleasedtoberelaunchingourpeer supportprogrammeMetabolicConnect!

Thisisourfreeprogrammewhich connectspeoplewiththesameorsimilar conditions,orothercommonalitieswith eachotheronaone-to-onebasis.

Peersupportopportunitieslikethiscan helptoreducefeelingsofisolationand provideaconnectionwithsomeonewho understands,appreciates,andhasdirect experienceoflivingwithorcaringfor someonewiththesameorsimilarIMD. Theseconnectionsdrivediscoveriesof commonexperiencesandconversations withpeoplewhojustgetit.

Ourrevisedprogrammeaimstoprovide moresupportfromourteamandgive youavoiceinhowtheservicedevelops andgrows.

Registerthroughourwebsite,here,to findoutmoreandjoin.Amemberofthe teamwillcontactyou.

Tuesday8thAugust5pm-6pm

Thursday24thAugust5pm–6pm

TravelandHolidaysChat: Toregistertojoinpleaseemailhelen@metabolicsupportuk.org

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GetInvolved

How to support us to support others

MetabolicSupportUKcouldn'texistwithoutyouandweaimtodoevenmoreinthefuture toensureanyoneaffectedbyanInheritedMetabolicDisorderisseen,heardandsupported.

We'reregisteredwitheasyfundraising,whichmeansyoucanhelpus forFREE.Over7,000brandswilldonatetouswhenyouuse easyfundraisingtoshopwiththem–atnoextracosttoyourself.All youneedtodoissignupandremembertouseeasyfundraising wheneveryoushoponline.

It’seasyandcompletelyFREE!Thesedonationsreallymountup,so pleasesignuptosupportus:

Asalwaysyoucandonate,fundraise,orvolunteertohelpenable theworkwedo.Clickhereformoreinfoonhowtogetinvolved.

Looking for a challenge?

Doyoufancychallengingyourselfwhilstraisingvital fundsforusandtheworkwedo?

Whynotjoinusforthe2024LondonMarathon

Whetheryou'renewtofundraisingandmarathonsor havelotsofexperience,we'dlovetohearfromyou. We'reheretosupportyoualongyourjourney,withthe wholecommunitycheeringyouon!

Wehavelimitedspacesavailable,somakesuretofill inourapplicationformassoonasyoucanifyou're interestedinjoiningTeamMSUK.

Youcanfindourapplicationformonourwebsite:

2024LondonMarathonApplicationForm

SignUpHere
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Youarealwayswelcometoreachouttotheteam atMetabolicSupportUK,inawaythatsuitsyou.You cancallourfreephonehelplineMonday-Friday,10am-4pm, fillinthecontactformonourwebsite,orsendusanemail.

GetInvolved Page20 @MetabolicSupportUK @weareMSUK @MetabolicSupportUK P D I X C L V S B G R V X J N A I J K E R V T R I A L A X T H E L D M E E C Q L W F E G C A T Q J P U P S L U C S K T S C L A D O V T R E I O O V C J V B M Y W Q R O O A N W U U W C D M H E X A L S T R I K W C O T O L R B N P L A E C C W Y N H N X M J S K N I A I H A C N E I Y E J P C B J V F N F L E R A X N P L U U U Q E F H E C A P O T D A U O R K W R Y C T P M R N A N G Q E G L Q F F C Y P S O L T D M A K U J U X P C F J G E N E T I C E O N U Get in touch
act@metabolicsupportuk.org
.metabolicsupportuk.org
lic Support UK is a charity registered in England and Wales (1089588) in Scotland (SCO44634) and a Company Limited by Guarantee (04267454) 6523181 ia t erment h y ant

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