understanding gene and cell therapy approaches for dmd november 6 2015
TRANSCRIPT
![Page 1: Understanding Gene and Cell Therapy Approaches for DMD November 6 2015](https://reader036.vdocument.in/reader036/viewer/2022062309/5697bfb51a28abf838c9d968/html5/thumbnails/1.jpg)
Understanding Gene and Cell Therapy Understanding Gene and Cell Therapy Approaches for DMDApproaches for DMD
November 6 2015November 6 2015
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Overview
Annemieke Aartsma-Rus
• What does dystrophin do?
• What happens when there is no dystrophin?
• How does drug development work
• What genetic approaches are in development to replace dystrophin?
• How do they work
• Challenges/opportunities
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Some basic biology: genes & proteins
Annemieke Aartsma-Rus
• Proteins are building blocks of our body
• Genes contain blueprint for proteins
• Mistake in gene mistake in protein
• Genes have a volume switch (protein only produced in proper tissue)
• Dystrophin protein has a function in muscle
• Mistake in dystrophin Problems in muscle
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Muscles
Annemieke Aartsma-Rus
• 30-40% of our body is muscle
• >750 different muscles
• Muscles can grow bigger or smaller
• Muscles use a lot of energy
• Only maintained when needed
• Muscles are damaged when used too much
• Muscles have efficient system to repair damage and prevent future damage (grow bigger)
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Muscle contraction
Annemieke Aartsma-Rus
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Muscle fibers
Annemieke Aartsma-Rus
SkeletonSkeleton
Connective tissueConnective tissue
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Dystrophin
Annemieke Aartsma-Rus
• Dystrophin provides stability to muscle fibers during contraction
• Connects skeleton of muscle fibers to connective tissues surrounding muscle fibers
• No dystrophin Connection lost
• Muscle more sensitive to damage
• Chronic damage: repair system cannot keep up
• Loss of muscle tissue and function
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Dystrophin
Annemieke Aartsma-Rus
DystrophinDystrophin
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Duchenne: no functional dystrophin
Annemieke Aartsma-Rus
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What happens without dystrophin
Annemieke Aartsma-Rus
InflammationRepair
Muscle damage
Fibrosis
Less blood flow Too much Ca2+
Oxidative stress Mitochondria damaged
Loss of muscle tissueLoss of muscle function
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What are muscle cross sections?Muscle cross sectionsMuscle cross sections
Annemieke Aartsma-Rus
H&E stainingH&E stainingFibers pinkFibers pinkNuclei blueNuclei blue
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Dystrophin stainingDystrophin immune staining
Annemieke Aartsma-Rus
Healthy Mdx mouse Duchenne
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Revertant fibers & trace amounts
Annemieke Aartsma-Rus
Revertant Fibers
Trace amounts
Untreated DMD muscle
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Western blotting
Western blotWestern blot• Proteins isolated from muscleProteins isolated from muscle• Separated by sizeSeparated by size• Stain for dystrophinStain for dystrophin
Annemieke Aartsma-Rus
DMDDMD Becker (dilutions)Becker (dilutions) Control (diluted)Control (diluted)LongLong
ShortShort
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Therapy development
Annemieke Aartsma-Rus
• Dystrophin is missing• Trying to replace dystrophin
• Also many other therapies aiming at improving muscle quality/slowing down disease processes
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What are cell models
Annemieke Aartsma-Rus
• Cells derived from patients • Muscle biopsies• Skin biopsies converted into muscle cells (lab)
• Expanded in the lab (limited!!)• “Immortalized” cells
• Muscle stem cells treated with viruses• Keep expanding, but have been modified
• Cell cultures are model systems• Valuable tool for early stages of research
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What are mdx mice?
Annemieke Aartsma-Rus
Mdx mouse• Mutation in mouse dystrophin gene• No dystrophin protein• But….disease not very severe
• Very efficient muscle regeneration• Turns up volume switch utrophin gene in muscle
• No dsytrophin & utrophin: severe disease• (Double knockout mouse)
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Other animal models
Annemieke Aartsma-Rus
Golden retriever muscular dystrophy (GRMD)• Mutation in dog dystrophin gene• No dystrophin protein• Mutation beginning gene• Severe disease (muscle & heart)• Muscle weakness, remain ambulant• Most dogs do not live > year • Severity is variable
• Rare mild individuals
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Other animal models
Annemieke Aartsma-Rus
Pig model• Mutation in pig dystrophin gene• No dystrophin protein• Deletion exon 52• Severe disease (muscle & heart)
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Drug testing in patients
Annemieke Aartsma-Rus
• Test compound properties• Taken up by tissues efficiently?• How quickly cleared from the body?
• Test compound for efficacy• Does it work?• At which dose?
• Test compound for safety• Are there side effects?• At which dose?• Are they tolerable?
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Development of therapies
Annemieke Aartsma-Rus
• Tests from cell and animal models to clinical trials
• All steps are important to show proof-of-concept (does it work in a model system ?)
• Next steps are always more complicated
• Success in one step is no guarantee for success in subsequent steps
• Clinical trials are experiments in humans
• May not work, may not be safe
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Cell therapy
Annemieke Aartsma-Rus
Muscle stem cells• Isolate muscle stem cells from healthy donor
• Expand outside the body (culture in lab)
• Transplant into patients
• Transplanted cells repair muscle
• Transplanted cells make dystrophin
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Muscle stem cells (myoblasts)
Annemieke Aartsma-Rus
• Immune response (suppress)• Do not exit circulation after injection• Local injection: stay close to injection site• Tremblay (Canada): multiple local injections
• Local dystrophin restoration• Not feasible for larger muscles
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Stem cell therapy
Annemieke Aartsma-Rus
Stem cells from fat, bone and bloodvessel walls • Can exit bloodstream and migrate into muscle• Very low efficiency
Mesangioblasts most promising• Encouraging results in dog model• Safety trial ongoing in Italy (Giulio Cossu) • 3 patients received stem cells• Some side effects• Preparing for injection 2 more patients
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Niche
Annemieke Aartsma-Rus
InflammationRepair
Muscle damage
Fibrosis
• Dystrophic muscle is damaged (scar tissue/fibrosis)• The few transplanted stem cells that reach muscle
• Do not receive proper signals to become muscle• Receive signals from scar tissue: more fibrosis
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Immunity
Annemieke Aartsma-Rus
• Transplanting cells from one person to another will elicit an immune response
• Need chronic immune suppression
• Side effects
• Isolate patient stem cells, expand in the lab, correct mutation with gene therapy & transplant
• No immune response
• Gene therapy more efficient in cultured cells than in muscles
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Cell therapy summary
Annemieke Aartsma-Rus
• Opportunities
• Applicable to all patients
• Deliver dystrophin gene and repair muscle
• Currently in very early stage clinical development
• Challenges
• Efficiency very low
• Damaged muscle gives wrong signals to cells
• Immunity (only with allogenic transplantation
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Gene Therapy
Annemieke Aartsma-Rus
• Add functional gene to muscle cells patients
• Dystrophin protein made from new gene
• Applicable to ALL patients
• Genes located in nucleus cells
• How to get gene into (majority) nuclei of muscle cells?
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Gene Therapy
Annemieke Aartsma-Rus
Maaike van Putten
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Gene Therapy
Annemieke Aartsma-Rus
Virus
• Small organism that injects genetic information into cells
• Use to deliver dystrophin gene
• Adapt
• Remove virus genes (pathogenic)
• Add new gene (dystrophin)
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Gene Therapy
Annemieke Aartsma-Rus
Which virus?
• Most viruses do not infect muscle tissue
• Muscle cells do not divide often
• Lot of connective tissue (filters out viruses)
• Exception: adeno-associated virus (AAV)
• Preference for muscle
• Not pathogenic in man
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Gene Therapy
Annemieke Aartsma-Rus
• Very small (20 nm, 0.00002 mm)
• Capacity: 4.500 DNA subunits
• Dystrophin gene: 2.200.000 DNA subunits
• Genetic code gene: 14.000 subunits
• Remove part from genetic code
• Only essential parts remain
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Gene Therapy
Annemieke Aartsma-Rus
MicrodystrophinOnly crucial domainsFits in AAV particle
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Gene Therapy
Annemieke Aartsma-Rus
Clinical trials
• Safety study in 6 Duchenne patients
• 2006/7, USA: local injection biceps (Mendell,Samulski, Xiao Xiao)
• Immune response!
• Dystrophin in 2/6 patients (very low levels)
• Prepare for bigger trial (whole muscle treatment)
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Upscaling
Annemieke Aartsma-Rus
• Mouse 12 gram muscle
• Monkey 4 kg muscle
• Human boy 10-25 kg muscle
• Monkeys and humans much larger than mice
• Need much more viruses
• Manufacturing systems optimized to allow production of sufficient amounts for treating human limbs at clinical grade
333x
2-6x
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Delivery
Annemieke Aartsma-Rus
• Whole animal delivery possible for mouse
• Not feasible (yet) for large animals
• Limited by amount of virus
• Produced
• Injected
• Whole limb delivery in development for human
• Hydrodynamic limb perfusion (most efficient)
• Regional limb perfusion (less damage)
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Limb perfusion
Annemieke Aartsma-Rus
• Tested in monkeys and dogs with ‘color gene’
• Delivery to multiple muscles feasible
• Tested in adult MD patients with saline
• Possible for lower leg or arm (less efficient)
• Not yet tested in humans to deliver gene
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Gene Therapy Summary
Annemieke Aartsma-Rus
• Opportunities
• Applicable to all patients
• Currently in early clincial development (safety/tolerability tests)
• Challenges
• Microdystrophin only partially functional
• Delivery
• Immunity
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Gene/cell therapy: DNA editing
Annemieke Aartsma-Rus
• DNA has a repair system
• Activated upon DNA damage
• Use this system to correct for DNA mistakes?
Mutation
Template with correct DNA information
DNA repair system
Mistake corrected (in one cell)
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DNA editing
Annemieke Aartsma-Rus
• Challenge: DNA repair system very inefficient (1 in 1,000,000 – 1,000,000,000 cells)
• Much more efficient when DNA is ‘broken’ (1 in 10-1000 cells)
Have to generate DNA breaks at/close to mutation
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DNA scissor system
Annemieke Aartsma-Rus
• DNA scissors can cut DNA at specific location
Scissor cuts at/near mutation
Repair break with template(Correct small mutations)
Repair break without templateSmall mutations will be introduced (can correct genetic code like exon skipping)
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DNA scissor system
Annemieke Aartsma-Rus
Combination of DNA scissors to restore genetic code
Scissors cut around exon break is repaired
Exon is deleted Genetic code restored (like exon skipping)
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DNA scissor system
Annemieke Aartsma-Rus
• DNA scissors can make breaks in DNA
• Different types of scissors in development
• Zinc Fingers, TALENs and RGNs
• Challenge: deliver scissors and templates to muscles
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Exon skipping
Annemieke Aartsma-Rus
NormalNormal DuchenneDuchenne
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Dystrophin gene
Annemieke Aartsma-Rus
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Splicing
Annemieke Aartsma-Rus
ExonsExons IntronsIntrons1
3
5
6
7 Gene (DNA)Gene (DNA)
RNA copy (pre mRNA)RNA copy (pre mRNA)
messenger RNAmessenger RNA
1 - - - - - - - - - 79
dystrophin proteindystrophin protein
SplicingSplicing
2
4
3 4 56 7
1 21 2 3 4 5 6 7 8
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Duchenne: genetic code disrupted
Annemieke Aartsma-Rus
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Duchenne: genetic code disrupted
Annemieke Aartsma-Rus
Protein translation stops prematurelyProtein translation stops prematurely
Dystrophin not functionalDystrophin not functional
Exon 46 Exon 47 Exon 51 Exon 52?
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Becker: genetic code maintained
Annemieke Aartsma-Rus
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Becker: genetic code maintained
Annemieke Aartsma-Rus
Protein translation continuesProtein translation continues
Dystrophin partly functionalDystrophin partly functionalLess damageLess damage
Exon 46 Exon 47 Exon 52 Exon 53
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Exon skipping: restore genetic code
Annemieke Aartsma-Rus
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Applicability
Annemieke Aartsma-Rus Aartsma-Rus Hum Mutat 2009, 30:293-9
hotspot
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Exon skip chemistries
Annemieke Aartsma-Rus
• Two chemistries in clinical development
• GSK/Prosensa: 2’-O-methyl phosphorothioate (drisapirsen)
• AVI-Biopharma/Sarepta: phosphorodiamidate morpholino oligomers (eteplirsen)
• Exon 51
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Exon skipping summary
Annemieke Aartsma-Rus
• Opportunities
• AON delivery easier than genes/cells
• Clinical trial results encouraging
• Challenges
• Mutation specific approach
• Need to develop many AONs to treat majority of patients
• Repeated treatment needed (also opportunity)
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Stop codon readthrough
Annemieke Aartsma-Rus
1 79
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PTC124/ataluren
Annemieke Aartsma-Rus
1 79
PTC
Cell ignores new stop signalCell ignores new stop signalComplete protein is madeComplete protein is made
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Stop codon readthrough summary
Annemieke Aartsma-Rus
• Opportunities
• Oral delivery
• Applicable to multiple diseases
• Challenges
• Mutation specific approach (15%)