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>>> PRESS RELEASE Proof of Concept: Gene therapy for mitochondrial diseases Mitochondrial disease is now thought to be the second most commonly diagnosed genetic disease worldwide, and, unfortunately, there are still no proven treatment strategies for those diagnosed. Scientists from the Max Planck Institute for Biology of Ageing in Cologne were involved in collaborations to apply gene-therapy approaches in mice to successfully treat an animal model of mitochondrial disease. This may pave the way for future therapeutic strategies for patients. Every step we take, every laugh we make, every word we say requires energy. Mitochondria play a central role in our metabolism and energy production. Consequently, mitochondrial dysfunction causes a remarkably diverse group of metabolic diseases with a broad range of symptoms leading to severe disability. “Since the 1980s it was known that mutations in the mitochondrial DNA can lead to disease” explains James Stewart, group leader at the Max Planck Institute for Biology of Ageing and continues “we have known of these patients for over 30 years and only now are we starting to develop treatments”. A remarkable feature of mitochondria is that they contain their own DNA. Mutations in this mitochondrial DNA (mtDNA) can lead to mitochondrial diseases, but whether a person with a mutation develops disease or not is more complex. Many copies of mtDNA are present in each of our cells and, normally, disease-causing mutations are present in only a fraction of them. However, if the fraction of mutated mtDNA molecules rises above a certain threshold, mitochondrial function is compromised resulting in mitochondrial disease. Therefore, reducing the levels of mutated mtDNA molecules is a

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Page 1: PRESS RELEASE Proof of Concept: Gene therapy for ... · these mitochondrial diseases. And since there is a link between mitochondrial dysfunction and other conditions like Alzheimer’s

>>> 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

Page 2: PRESS RELEASE Proof of Concept: Gene therapy for ... · these mitochondrial diseases. And since there is a link between mitochondrial dysfunction and other conditions like Alzheimer’s

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.

Page 3: PRESS RELEASE Proof of Concept: Gene therapy for ... · these mitochondrial diseases. And since there is a link between mitochondrial dysfunction and other conditions like Alzheimer’s

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.

Page 4: PRESS RELEASE Proof of Concept: Gene therapy for ... · these mitochondrial diseases. And since there is a link between mitochondrial dysfunction and other conditions like Alzheimer’s

contact:

Author: Dr.JamesStewart PressandPublicRelations:

MaxPlanckInstituteforBiologyofAgeing Dr.AnnegretBurkert

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

E-Mail: [email protected] E-Mail:[email protected]

www.age.mpg.de


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