press release proof of concept: gene therapy for ... · these mitochondrial diseases. and since...

>>> PRESSRELEASE

ProofofConcept:Genetherapyformitochondrialdiseases

Mitochondrialdiseaseisnowthoughttobethesecondmostcommonlydiagnosed

geneticdiseaseworldwide,and,unfortunately,therearestillnoproventreatment

strategiesforthosediagnosed.ScientistsfromtheMaxPlanckInstituteforBiology

ofAgeinginColognewereinvolvedincollaborationstoapplygene-therapy

approachesinmicetosuccessfullytreatananimalmodelofmitochondrial

disease.Thismaypavethewayforfuturetherapeuticstrategiesforpatients.

Everystepwetake,everylaughwemake,everywordwesayrequiresenergy.

Mitochondriaplayacentralroleinourmetabolismandenergyproduction.

Consequently,mitochondrialdysfunctioncausesaremarkablydiversegroupof

metabolicdiseaseswithabroadrangeofsymptomsleadingtoseveredisability.“Since

the1980sitwasknownthatmutationsinthemitochondrialDNAcanleadtodisease”

explainsJamesStewart,groupleaderattheMaxPlanckInstituteforBiologyofAgeing

andcontinues“wehaveknownofthesepatientsforover30yearsandonlynowarewe

startingtodeveloptreatments”.

AremarkablefeatureofmitochondriaisthattheycontaintheirownDNA.Mutationsin

thismitochondrialDNA(mtDNA)canleadtomitochondrialdiseases,butwhethera

personwithamutationdevelopsdiseaseornotismorecomplex.ManycopiesofmtDNA

arepresentineachofourcellsand,normally,disease-causingmutationsarepresentin

onlyafractionofthem.However,ifthefractionofmutatedmtDNAmoleculesrises

aboveacertainthreshold,mitochondrialfunctioniscompromisedresultingin

mitochondrialdisease.Therefore,reducingthelevelsofmutatedmtDNAmoleculesisa

potentialtreatmentstrategy.

However,thistreatmentstrategyisnotsostraightforwardasconventionalgene-therapy

approachesdonotworkinmtDNA.ScientistsfromtheUniversityofCambridge,UKand

theUniversityofMiami,USA,developedanapproachtospecificallydegrademutated

mtDNAmoleculesincellculture.Usingamodifiedvirus,theydeliveredageneintothe

cellnucleusthatencodesaproteinthatworksasmolecularscissors.Thesemolecular

scissorsarethenproducedbythecellandtargetedtomitochondria,wherethey

specificallycutthemutatedmtDNA.

Butwouldthemethodalsoworkincomplexorganismscomposedofmanytissueslike

miceorhumansandactuallytreatmitochondrialdisease?Stewartandhiscolleaguesin

Colognecouldprovidetheanswer.Theyhadgeneratedamousemodelofmitochondrial

diseasethatcontainsaspecificdisease-causingmutationinmtDNAwhichleadsto

disordersincardiacandmusculartissue.Theytreatedtheanimalswiththevirusthat

onlyinfectedtheheartorthemuscles.Thevirusdeliveredthemolecularscissortocut

themutatedmtDNAinthetargetedtissue.Andinfact,theapproachworked!Thelevels

ofmutatedmtDNAwerereducedandthediseasesymptomswerealleviated.

“Thisisthefirstgenetherapytoactuallyremovethecauseofamitochondrialdiseasein

alivinganimal”adelightedStewarttellsus.Ofcourse,beforethetherapycanbeapplied

tohumanpatientsmoredetailedworkandsafetyassessmentsmustbedone.

Nevertheless,thescientistscouldprovethattheyfoundawaytoremovethecauseof

thesemitochondrialdiseases.Andsincethereisalinkbetweenmitochondrial

dysfunctionandotherconditionslikeAlzheimer’sdisease,Parkinson’sdisease,diabetes,

andperhapssomecancers,theapproachwillmightevenhaveahigherimpactin

fightingthosedisordersinthefuture.

Pressphoto:

Avirus-infectedcellinacellculturesurroundedbyuninfectedcells.Mitochondriaare

showningreen.Thevirusshowninorange-red(leftcell)islocatedtothemitochondria.

Scalebars:10μm(©MitochondrialBiologyUnit,UniversityofCambridge)

ApicturerequestcanbesentbyE-Mailortelephone.PleasecontactDr.Annegret

Burkert,youcanfindthecontactdetailsbelow.

Originalpublication:

PayamA.Gammage,CarloViscomi,Marie-LuneSimard,AnaS.H.Costa,EdoardoGaude,

ChristopherA.Powell,LindseyVanHaute,BeverlyJ.McCann,PedroRebelo-Guiomar,

RaffaeleCerutti,LeiZhang,EdwardJ.Rebar,MassimoZeviani,ChristianFrezza,JamesB.

StewartandMichalMinczuk:Genomeeditinginmitochondriacorrectsapathogenic

mtDNAmutationinvivo.NatureMedicine,2018DOI:10.1038/s41591-018-0165-9.

and

SandraR.Bacman,JohannaH.K.Kauppila,ClaudiaV.Pereira,NadeeNissanka,Maria

Miranda,MelinaPinto,SionL.Williams,Nils-GöranLarsson,JamesB.Stewartabd

CarlosT.Moraes:MitoTALENreducesmutantmtDNAloadandrestorestRNAAlalevelsin

amousemodelofheteroplasmicmtDNAmutation.NatureMedicine,DOI:

10.1038/s41591-018-0166-8.

contact:

Author: Dr.JamesStewart PressandPublicRelations:

MaxPlanckInstituteforBiologyofAgeing Dr.AnnegretBurkert

Phone: +49(0)22137970706 Phone:+49(0)22137970207

E-Mail: JStewart@age.mpg.de E-Mail:ABurkert@age.mpg.de

www.age.mpg.de