2017 BDSRA Cooper, Nelvagal, Egeland, Najafi, Assis and Repschlager CLN1, CLN2, CLN3
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Thinking outside the brain for Batten disease What goes wrong in Batten Disease? Mistakes or mutations in DNA are passed on from generation to generation This means that proteins in the lysosome that have crucial jobs either don’t get made or are defective X X Mutation The lysosome acts as the cell’s ‘recycling center’ Lysosomes Cell Lysosome It helps to break down and reuse ‘unwanted’ or defective proteins X TransmembraneProteins Lysosomal Enzymes X Infantile NCL (CLN1) Late-InfantileNCL (CLN2) Juvenile NCL (CLN3) How does this lead to disease? Build-up of un- degraded material Batten Disease Nervous system affected How can we treat these diseases? The brain and body are affected The location and order in which different parts of the body are affected The Brain and spinal cord Not all parts of the brain are affected to the same extent. This is true of many forms of NCL including CLN1, CLN2, CLN3, CLN6 and CLN7. Mouse Brain Human Brain This is seen in mouse and human brains We now know that the spinal cord is also significantly affected Spinal cord How does this affect movement? In Infantile NCL (CLN1), the spinal cord is affected before the brain Defective or missing Proteins Parts of the body outside the nervous system are also affected Heart defects Liver defects Are other peripheral nerves affected? Are nervous system connections faulty? Can directly inform where, when and how treatments are to be delivered Targeted Treatments Treating the brain and spinal cord Maybe a combination of all of these? Replace the missing/defective enzyme. Enzyme delivered only to the spinal cord showed mild improvements in brain and spinal cord disease. (Possible only for enzyme-deficient NCLs) Replace the missing/defective gene. Can be possibly be used for ALL NCL types - Combined to treat BRAIN and SPINAL CORD. Gene Vector Brain Spinal Cord Enzyme Brain Spinal Cord Best results of any treatment to date for Infantile NCL (CLN1). Work is now ongoing for this treatment in other forms of NCL. Scaling up Promising treatments in mice must now be scaled up to test in large animals before clinical trials. CLN1, CLN2, CLN3 and others… Jon Cooper (PI), Hemanth Nelvagal, Martin Egeland, Allison Najafi, Ana Assis, Charlott Repschlager(KCL) Pediatrics, Los Angeles Biomedical Research Institute, David Geffen School of Medicine, UCLA. Approved as a treatment for CLN2, but we are trying to do the same for CLN1
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Transcript of 2017 BDSRA Cooper, Nelvagal, Egeland, Najafi, Assis and Repschlager CLN1, CLN2, CLN3
ThinkingoutsidethebrainforBattendisease
What goes wrong in Batten Disease?
Mistakesormutations inDNA arepassedonfromgenerationtogeneration
Thismeansthatproteins inthelysosome thathavecrucialjobseitherdon’tgetmadeoraredefective
X X
Mutation
Thelysosome actsasthecell’s‘recyclingcenter’
Lysosomes
Cell Lysosome
Ithelpstobreakdownandreuse‘unwanted’ordefectiveproteins
XTransmembraneProteinsLysosomalEnzymes
X InfantileNCL (CLN1)Late-InfantileNCL(CLN2) JuvenileNCL(CLN3)
Howdoesthisleadtodisease?
Build-upofun-degradedmaterial
BattenDisease
Nervoussystemaffected
Howcanwetreatthesediseases?
The brain and body are affected
Thelocation andorder inwhichdifferentpartsofthebodyareaffected
TheBrainandspinalcord
Notallpartsofthebrain areaffectedtothesameextent.
ThisistrueofmanyformsofNCLincludingCLN1,CLN2,CLN3,CLN6and
CLN7.
MouseBrain HumanBrain
Thisisseeninmouseandhumanbrains
Wenowknowthatthespinalcordisalsosignificantlyaffected
Spinalcord
Howdoesthisaffectmovement?
InInfantileNCL(CLN1),thespinalcordisaffectedbeforethebrain
DefectiveormissingProteinsPartsofthebodyoutsidethe
nervoussystemarealsoaffected
Heartdefects Liverdefects
Areotherperipheralnervesaffected?
Arenervoussystemconnectionsfaulty?
Candirectlyinformwhere,when andhowtreatmentsaretobedelivered
TargetedTreatments
Treating the brain and spinal cord
Maybeacombination ofallofthese?
Replace themissing/defectiveenzyme.
Enzymedeliveredonly tothespinalcordshowedmildimprovements in brainand spinalcorddisease.
(Possibleonlyforenzyme-deficientNCLs)
Replace themissing/defectivegene.
CanbepossiblybeusedforALL NCLtypes- CombinedtotreatBRAIN andSPINAL CORD.
Gene
Vector
Brain
SpinalCord
Enzyme
Brain
SpinalCord
Bestresults ofanytreatmenttodateforInfantileNCL(CLN1).
WorkisnowongoingforthistreatmentinotherformsofNCL.
Scalingup
Promisingtreatmentsinmicemustnowbescaleduptotestinlargeanimalsbeforeclinicaltrials.
CLN1,CLN2,CLN3
andothers…JonCooper(PI),Hemanth Nelvagal,MartinEgeland,AllisonNajafi,AnaAssis,Charlott Repschlager(KCL)Pediatrics,LosAngelesBiomedicalResearchInstitute,DavidGeffenSchoolofMedicine,UCLA.
ApprovedasatreatmentforCLN2,butwearetryingtodothesameforCLN1
