overview of duchenne research strategies
DESCRIPTION
Overview of Duchenne Research Strategies by Sharon Hesterlee at PPMD's 2010 Annual Connect ConferenceTRANSCRIPT
Introduc)on to Therapeu)c Strategies for Duchenne
Sharon Hesterlee, Ph.D. Sr Director Research and Advocacy
DMD develops when dystrophin is missing or malformed
What does dystrophin do?
What happens when dystrophin is missing?
calcium
Free radicals Inflamma)on Fibrosis (scarring) Muscle cell death
no linkage
Strategies: How to fix the problem?
• Gene repair
• Gene replace-‐ ment (gene therapy)
• Stop codon read-‐ through
• PTC drugs to upregulate utrophin and IGF-‐1 and to block myostaFn
Membrane integrity Cell health NO signaling
Gene Muscle Cell RNA Protein Downstream funcFons
• Stem cells
• Increase muscle growth
• Protein replacement
• Nitric oxide enhancers
• Cell death inhibitors
• Protein break-‐ down blockers
• InflammaFon blockers
• Exon-‐skipping
Basic Research Drug Screening Target IdenFficaFon
“Proof-‐of-‐Principle” TesFng in Animals
TranslaFonal Research “Preclinical Drug Development”
Clinical Research Including Trials
From the “Bench” to the “Bedside”
Number of Projects
Cost of Projects
Pipeline
Poloxamer therapy Myoblast Transplant
Cardiac Repair Exercise
Growth Factors Dystrophin S)mula)on Utrophin Upregula)on Cord Blood Stem Cells
Muscle Growth Bone Marrow Stem Cells
Embryonic Stem Cells
Utrophin Protein Therapy
Mesangioblast Stem Cells
Non-‐viral Gene Therapy
Gene Correc)on
An)-‐inflamma)on
Gene Therapy: Regional PTC-‐124
Exon-‐skipping
Gene Therapy: IM
An)-‐fibro)c Therapy
Proof of concept Preclinical Human Trials
Phase I Phase II
Strategies: How to fix the problem?
• Gene repair
• Gene replace-‐ ment (gene therapy)
• Stop codon read-‐ through
• PTC drugs to upregulate utrophin and IGF-‐1 and to block myostaFn
Membrane integrity Cell health NO signaling
Gene Muscle Cell RNA Protein Downstream funcFons
• Stem cells
• Increase muscle growth
• Protein replacement
• Nitric oxide enhancers
• Cell death inhibitors
• Protein break-‐ down blockers
• InflammaFon blockers
• Exon-‐skipping
TherapeuFc Strategies: Supplying healthy genes
• Dystrophin • Utrophin • Agrin • Integrin • GalNac transferase • LARGE
[Illustra)ons from MDA’s Quest Magazine]
TherapeuFc Strategies: Supplying healthy genes
Who Phase Gene Vector Delivery Status
Plasmid study (Fardeau, et al) 2004
Phase I Dystrophin Plasmid Intra-‐muscular injec)on
Complete: weak dystrophin in of 9 par)cipants
Asklepios Biopharmaceu)cals (Mendell and Samulski) 2010
Phase I Micro-‐Dystrophin
AAV 2.5 Intra-‐muscular injec)on
complete
Mendell-‐Wilton Phase I Alpha-‐sarcoglycan (LGMD)
AAV 2 Intramuscular injec)on
complete
Mendell Phase II Alpha-‐sarcoglycan (LGMD)
AAV8 Regional (whole limb)
enrolling
Samulski Phase II Micro-‐Dystrophin
AAV8 Regional (whole limb)
Healthy volunteers
Mendell Phase I FollistaFn (BMD and IBM)
AAV1 Intra-‐muscular injecFon
2011
Chamberlain Phase I Micro-‐dystrophin
Strategies: How to fix the problem?
• Gene repair
• Gene replace-‐ ment (gene therapy)
• Stop codon read-‐ through
• PTC drugs to upregulate utrophin and IGF-‐1 and to block myostaFn
Membrane integrity Cell health NO signaling
Gene Muscle Cell RNA Protein Downstream funcFons
• Stem cells
• Increase muscle growth
• Protein replacement
• Nitric oxide enhancers
• Cell death inhibitors
• Protein break-‐ down blockers
• InflammaFon blockers
• Exon-‐skipping
TherapeuFc Strategies: Exon-‐skipping
Intron Intron Intron Intron
exon exon exon
“frameshiZ” mutaFon in dystrophin RNA leads to garbled protein
Blocking splice site with anFsense oligos leads to exclusion of exon with mutaFon; protein is shorter, but in frame
TherapeuFc Strategies: Exon-‐skipping
Who Where Exon Phase Delivery Status
Prosensa Europe 51 PRO051
Phase I Intramuscular Complete
AVI UK 51 AVI-‐4658
Phase I Intramuscular Complete
GSK Europe 51 GSK2402968
Phase I/IIa Systemic Complete
AVI UK 51 AVI-‐4658
Phase II Systemic Final data analysis
AVI 50 AVI-‐5038
Preclinical Not in humans
Prosensa Europe 44 PRO044
Phase I/IIa Subcutaneous injec)on
Ongoing
Exon 51 skipping for these deleFons: exons 45-‐50, exons 47-‐50, exons 48-‐50, exons 49-‐50, exon 52 and exons 52-‐63 Exon 50 skipping for these deleFons: Exon 51, exons 51-‐53, exons 51-‐55
Therapeu)c Strategies: “Ignoring” muta)ons
STOP
STOP
STOP
Gentamicin/ PTC 124
STOP
Dystrophin protein fragment
Full-‐length dystrophin
Therapeu)c Strategies: “Ignoring” muta)ons
Who What Phase Delivery Status
Jerry Mendell Gentamicin Phase I/II IV Completed
PTC Therapeu)cs
Ataluren Phase I Oral Completed
PTC Therapeu)cs
Ataluren Phase IIa Oral Completed
PTC Therapeu)cs
Ataluren Phase IIb Oral Halted
PTC Therapeu)cs
Ataluren Non-‐ambulatory study
Oral Halted
Strategies: How to fix the problem?
• Gene repair
• Gene replace-‐ ment (gene therapy)
• Stop codon read-‐ through
• PTC drugs to upregulate utrophin and IGF-‐1 and to block myostaFn
Membrane integrity Cell health NO signaling
Gene Muscle Cell RNA Protein Downstream funcFons
• Stem cells
• Increase muscle growth
• Protein replacement
• Nitric oxide enhancers
• Cell death inhibitors
• Protein break-‐ down blockers
• InflammaFon blockers
• Exon-‐skipping
Muscle Build-‐up verses Muscle Break-‐down
• Block protein break-‐down (proteasome inhibitors) • Block cell death (apoptosis inhibitors) • S)mulate muscle
growth pathways
Who What Phase Delivery Status
Wyeth Myotas)n an)body
Phase I Subcutaneous Completed
Wyeth Phase I/II Subcutaneous Completed
Iplex Phase IIb IV Completed
Acceleron ACE-‐031 Phase I Injec)on Completed
Acceleron ACE-‐031 Phase II Injec)on Recrui)ng
Muscle Build-‐up verses Muscle Break-‐down
Therapeu)c Strategies: Supplying new cells
Entering Muscle
Stem Cells Derived from • Bone marrow • Muscle )ssue • Blood vessels • Embryos
Who What Where Phase Status
Guilio Cossu Mesangioblast transplant
Italy Phase I Preclinical
[illustra)on from MDA’s Quest Magazine]
An)-‐inflammatory/an)-‐fibro)c Strategies
• Prednisone • NF-‐κB pathway • TGF-‐beta pathway
Who What Phase Status
Ka)e Bushby: TREAT-‐NMD
Prednisone Approved Recrui)ng within the next year
Catabasis CAT-‐1904 (NF-‐κB ) Preclinical No human studies
Validus Anecortave (NF-‐κB) Preclinical No human studies
Dennis Gunridge NBD ( NF-‐κB ) Proof-‐of-‐concept No human studies
Jerry Mendell and Hugh Allen
Losartan (TGF-‐Beta) Approved Recrui)ng
Strategies: How to fix the problem?
• Gene repair
• Gene replace-‐ ment (gene therapy)
• Stop codon read-‐ through
• PTC drugs to upregulate utrophin and IGF-‐1 and to block myostaFn
Membrane integrity Cell health NO signaling
Gene Muscle Cell RNA Protein Downstream funcFons
• Stem cells
• Increase muscle growth
• Protein replacement
• Nitric oxide enhancers
• Cell death inhibitors
• Protein break-‐ down blockers
• InflammaFon blockers
• Exon-‐skipping
Other Approaches
• Restoring Nitric Oxide (NO) ac)vity in the muscle
• Patching holes in the membrane
• Blocking calcium
• Reducing oxida)ve stress
• “Membrane stabilizing” proteins (utrophin, laminin 111, agrin, GalNac transferase)
Who What Phase Status
Kathryn Wagner and Stan Froehner
Sildenafil (NO restora)on)
Approved Recruitment this year
Phrixus Carmaseal (poloxamer 188) for cardiomyopathy
Preclinical Recruitment this year
Fred Sachs of SUNY Buffalo and Rose Pharmaceu)cals
GsMTx4 Mechano-‐sensi)ve pore blocker
Proof-‐of-‐concept No human studies
Brian Tseng Protandim (reducing oxida)ve stress)
Supplement No humans studies in DMD
Prothelia Laminin 111 Preclinical—Lead candidate
No human studies
Biomarin Utrophin upregulator Phase I In progress
Jim Ervas), University of Michigan
TAT-‐utrophin Proof-‐of-‐concept No human studies
PTC Therapeu)cs Utrophin upregulator Preclinical—lead candidate
No human studies
Other Approaches
Sharon Hesterlee, Ph.D. Senior Director of Research and Advocacy
Parent Project Muscular Dystrophy
[email protected] (520) 444-‐4462
Ques)ons?