ScottSullivanFellowship20196MonthProgressReportDrShyuanNgo

QueenslandBrainInstitute14June2019

Scott Sullivan Fellowship 2019 6 Month Progress Report Dr Shyuan Ngo 2

Overview

As theScott SullivanMNDResearchFellow, Ioverseea teamof researcherswhoare conductingtranslationalresearchacrossTheUniversityofQueensland(UQ)andTheRoyalBrisbane&Women’sHospital (RBWH). The laboratory where my team conduct all of our benchwork is based in theAustralianInstituteforBioengineeringandNanotechnology(AIBN)attheUQStLuciacampus.Ourclinicalresearch isbasedattheRBWH,andtheCentreforClinicalResearch(UQ),whicharebothlocatedattheHerstonCampus.

Myteam’sclinicalresearchfocusesongeneratingabetterunderstandingofhowthebodyrespondstoMND,andwhy thismightbedifferentbetweenpatients.Workingwithpatients,westudy therelationshipbetweenenergysupplyanduse,dietaryintake,gutfunction,physicalactivityanddiseaseprogression.Bystudyingmultipleaspectsofphysiology,ourgoalistounderstandMNDonapatient-by-patientbasis.Ourclinical research is supportedbya strongcollaborativenetwork. Locally,wework closelywith A/Prof Robert Henderson and Prof PamelaMcCombe at the Royal Brisbane&Women’s Hospital and Wesley Hospital. To broaden the international reach and impact of ourresearch,andtobuildcapacitytoestablishanenduringframeworkthatwillsupportthetranslationofourresearchintofutureclinicaltrials,Ihaveestablishedcollaborationswithtwointernationallyrecognisedandhighly-regardedMNDneurologistsintheNetherlands(ProfLeonardvandenBerg)andtheUnitedKingdom(ProfAmmarAl-Chalabi).

My team’s laboratory-based research aims to identify themechanisms that causeMND, and themolecularchangesthatoccurasaconsequenceofMND,sothatwecan identify targets fordrugdevelopment.Necessarily,ourlaboratory-basedresearchisalsohighlycollaborative,supportingmyvisiontodeliverresearchfindingsthatareclinicallymeaningful.WeworkwithresearchersacrossAustralia, France, Italy, USA, and China who have expertise in drug development, physiology,biochemistry,genetics,statistics,andstemcells.

ResearchUpdate

Clinicalresearch:

In2018,wepublishedthefirstresultsfromourpatientstudies,showingthathypermetabolism(whenenergyuseishigherthanwhatisexpected)occursinMNDpatientswhohavefasterfunctionaldeclineand thathypermetabolicMNDpatientsareat riskofearlierdeath.Paradoxically, this increase inmetabolismwasnot relatedtoweight loss,which is thought tobeamajorcontributing factor tofasterdiseaseprogressioninMND.

TounderstandwhychangesinmetabolismmightbetheoccurringinMND,wehavebeenstudyingdietdiaryinformationandthegutmicrobiomeofeachpatienttounderstandifdietaryintakeandguthealthmightbelinkedtoincreasedenergyuseinMND.WeareinthefinalstagesofanalysingthisdataandourresultssuggestthattherearesignificantdifferencesbetweenthedietarycompositioninMNDpatientswhencomparedtonon-MNDindividuals,butthatthegutmicrobiomeappearstobe mostly unchanged. Collectively, these studies have now led to the development of a novelresearchprogrambyourcollaborator,DrFrederikSteyn,whoisinvestigatinghowchangesinappetiteanddietcanimpactweight lossandoverallenergybalanceinMND.Thiscollaborativeresearchis

Scott Sullivan Fellowship 2019 6 Month Progress Report Dr Shyuan Ngo 3

progressingwell;wehaverecentlypublisheddatatoshowthatabout30%ofMNDpatientshavereducedinappetite,andthatchangesinappetiteappeartobeaprimaryfactorforweightlossinMND.

Inourclinicalresearch,wearealsotrackingphysicalactivityinourpatientstoseeiftheenergythattheyareexpendingisbeingoffsetbytheamountandtypeoffoodthattheyareeating.AbenefittotrackingphysicalactivityinMNDpatientsisthatwearealsoabletoaskimportantresearchquestionsaboutfatigue.Wehavefoundthatabout70%ofourMNDpatientsexperienceseverefatigue,andwearenowaiming todevelopnewways tohelpMNDpatientsmanage their fatigue symptoms.Workingwith our Prof Leonard van den Berg’s group in theNetherlands,we are also aiming todeterminewhethertheuseofactivitytrackerscanbeusedameanstoremotelymonitordiseaseprogressioninMNDpatients.

A dynamic young researcher,MsDiana Lucia has recently joinedmy researchteam,andwillbeworkingcloselywithourMNDpatientsinthecomingyear.Shehasastrongresearchbackgroundincircadianrhythmsandwillbefurtherdrivingthis area of research within the team. Diana also has a strong sciencecommunication portfolio. Since joining the team, she has volunteered at anumberofMNDandMeFoundationevents,andwillbecontinuingtodothisinthefuture.

Iwould liketotakethisopportunitytothankalloftheMNDpatients,theircarersandfamilyandfriends,aswellasalloftheothervolunteerswhoare involvedinourresearch.Theworkthatmyteamdointheclinicwouldnotbepossiblewithoutyourcontributions.

Laboratory-basedresearch:

TodevelopabetterunderstandingofwhatmightbecausinghypermetabolisminMND,wehavebeencollectingblood,andmuscleandskinbiopsiesfromourMNDpatientsandcontrolvolunteers.WehavebeenstudyingthebloodtoseeifthereareanymoleculesthatmightexplainincreasedenergyuseinMND,andhavefoundchangesintheexpressioninanumberofhormonesthatregulateenergysupplyanduseinthebody.Inthecomingyear,wewillbeconfirmingthis observation in a larger set of samples.We have an enthusiastic young

scientist,MrCoryHoldom,whoiscurrentlyconductinghishonoursresearchprojectinthisareaofourresearch.

Withourmusclebiopsies,weareusingtheresidentstemcellsinthemuscletogeneratemusclefibresinadish.WehavebeenstudyingthewayinwhichthesemusclefibresuseandgenerateenergyandhavefoundthatmusclefibresfromMNDpatientsappeartousefatas a preferred fuel source. This is an interestingobservation because muscle usually prefers to usesugarasfuelsourcetogenerateenergy.Wearenowexpanding on these results to understand why this

changeinfuelpreferenceisoccurring,andhowthisrelatestothewaythatthebodyusesenergy.DrSiobhanKirk,apostdoctoralresearchfellowinmy

Siobhan Kirk

Elyse Wimberger

Diana Lucia

Cory Holdom

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labwhohasquicklymasteredtheskillsinthisarea,isoverseeingthispartoftheresearchwithsupportfromourresearchassistant,MsElyseWimberger.

Withtheskinbiopsies,weareturningskincellsintostemcellsthatwethenturnintoneurons.ThisworkisbeingledbyatrulyexceptionalPhDstudentinthegroupMrTimothyTracey,whoisalsoworkingcloselywithSiobhan.Morerecently,Timhasmasteredanewtechniquetoturnskincellsdirectlyintoneurons,makingusthefirstteaminAustraliatogeneratethesedirectlyreprogrammedneuronsforstudying MND. This new method is important because the resulting neuronsmaintainenvironmentalsignaturesthatcangiveusnewcluesintoenvironmentaltriggersformotorneurondeath.Similartoourmusclesamples,weareusingour

neuronstostudywhetherthewayinwhichtheyuseandgenerateenergyisrelatedtothechangesinthewaythebodyusesenergy,andwhetherthereareuniquedifferences inneuronsthathavebeengeneratedfromdifferentMNDpatients.WehopethatthisinformationcanhelpustodevelopmoretargetedtreatmentapproachesforeachMNDpatient.

Inthelaboratory,wealsousingmousemodelstotestanumberofdrugswiththeaimtoimprovefunctionandsurvival.AllofourmouseworkisoverseenbyDrTesfayeTefera,whohasover4yearsexperienceinstudyingmetabolisminmousemodelsofMND.Resultsfromallofourmouseprojectshavebeenpromising, andwe are now testing these same compounds in themusclefibresandneuronsthatwehavegeneratedfromourMNDpatients.

In the last 6 months, my team have been training anundergraduate researcher,MrHaoWang,whowillbecommencehishonoursresearchprojectlaterthisyear.Hao’sprojectwillbebasedacrossmylaboratoryandDrFrederikSteyn’slaboratory,andaimstotestanewcompoundthatbuildsonhistoricalworkconductedinmylaboratory,aswellasrecentobservationsthatwehavemadeintheclinic.

Overall, the young team of researchers in my laboratory have been workingtirelesslytoimproveourunderstandingofMND,andtotestwhetherthedrugswearerepurposingareapromising treatment approach forMND.Themajorityof thisworkhasbeen submitted forpresentationatthe30thInternationalALS/MNDSymposiuminPerthinDecember2019,andwearelookingforwardtogettingfeedbackfromourinternationalpeers.

IwouldliketothanktheMNDandMeFoundationandtheRBWHFoundationfortheirgenerosityandcontinuedsupportofmyresearch.IwouldalsoliketothanktheQueenslandBrainInstitute,andthe Australian Institute for Bioengineering and Nanotechnology for supportingmy research andmembersofmyteam.Thishasenabledmetoprogressmywork,andtoestablishastronggroupofdedicatedearlycareerresearcherswhoareallworkingtowardsourultimategoalofdevelopingadrugtherapytocombatMotorNeuroneDisease.

Tim Tracey

Tesfaye Tefera

Hao Wang

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Contact details

Dr Shyuan Ngo Scott Sullivan Research Fellow T +61 7 336 53847 E s.ngo@uq.edu.au W uq.edu.au

CRICOS Provider Number 00025B