Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment

Sebahattin Cirak, Virginia Arechavala-Gomeza, Michela Guglieri, Lucy Feng, Silvia Torelli, Karen Anthony, Maria Elena Garralda, Dominic J. Wells, George Dickson, Matthew Ja Wood, Stephen D. Wilton, Volker Straub, Stephen B. Shrewsbury, Caroline Sewry, Jennifer Morgan, Kate Bushby, Francesco Muntoni

Research output: Contribution to journalAbstractResearchpeer-review

Abstract

Objective: We report biochemical efficacy and clinical safety of
a phase 1b/2 dose-ranging study of IV administered AVI-4658,
an antisense morpholino oligomer which restores the reading
frame and enables dystrophin expression in Duchenne muscular
dystrophy (DMD) patients with amenable deletions for exon 51
skipping.
Method: AVI-4658 was given weekly for 12 weeks by intravenous
infusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and
20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. The
primary study objective was safety and tolerability over the
26 week study. Secondary objectives were: 1) pharmacokinetic
properties, 2) ability of AVI-4658 to induce exon skipping and
dystrophin expression by RT-PCR, immunohistochemistry and
immunoblotting.
Results: AVI-4658 was well tolerated with no drug related serious
adverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658
induced exon 51 skipping in the first 4 cohorts, followed by
both stronger skipping and dystrophin protein expression in a
generally dose dependent, but variable, manner in boys from
cohort 3 onwards. A total of 7 subjects displayed an increase of
dystrophin expression in the post-treatment biopsy, with 3 subjects
showing a substantial increase in positive fibers (15%, 21% and
55%, respectively). Additionally dystrophin associated proteins were
restored at the sarcolemma. Analysis of the inflammatory infiltrate
indicated a reduction of cytotoxic T cells in the post-treatment
muscle biopsies in the 2 higher dose cohorts.
Conclusion: We demonstrate the potential of AVI-4658 to become
a disease modifying drug in the treatment of DMD.
Original languageEnglish
JournalNeuromuscular Disorders
Publication statusPublished - 2011

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Morpholinos
Dystrophin
Duchenne Muscular Dystrophy
Exons
Biopsy
Dystrophin-Associated Proteins
Therapeutics
Safety
Sarcolemma
Pharmaceutical Preparations
Immunohistochemistry
AVI-4658
T-Lymphocytes
Muscles
Polymerase Chain Reaction
Proteins

Cite this

Cirak, Sebahattin ; Arechavala-Gomeza, Virginia ; Guglieri, Michela ; Feng, Lucy ; Torelli, Silvia ; Anthony, Karen ; Garralda, Maria Elena ; Wells, Dominic J. ; Dickson, George ; Wood, Matthew Ja ; Wilton, Stephen D. ; Straub, Volker ; Shrewsbury, Stephen B. ; Sewry, Caroline ; Morgan, Jennifer ; Bushby, Kate ; Muntoni, Francesco. / Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment. In: Neuromuscular Disorders. 2011.
@article{35b10177876248cba17ad153600801a0,
title = "Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment",
abstract = "Objective: We report biochemical efficacy and clinical safety ofa phase 1b/2 dose-ranging study of IV administered AVI-4658,an antisense morpholino oligomer which restores the readingframe and enables dystrophin expression in Duchenne musculardystrophy (DMD) patients with amenable deletions for exon 51skipping.Method: AVI-4658 was given weekly for 12 weeks by intravenousinfusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. Theprimary study objective was safety and tolerability over the26 week study. Secondary objectives were: 1) pharmacokineticproperties, 2) ability of AVI-4658 to induce exon skipping anddystrophin expression by RT-PCR, immunohistochemistry andimmunoblotting.Results: AVI-4658 was well tolerated with no drug related seriousadverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658induced exon 51 skipping in the first 4 cohorts, followed byboth stronger skipping and dystrophin protein expression in agenerally dose dependent, but variable, manner in boys fromcohort 3 onwards. A total of 7 subjects displayed an increase ofdystrophin expression in the post-treatment biopsy, with 3 subjectsshowing a substantial increase in positive fibers (15{\%}, 21{\%} and55{\%}, respectively). Additionally dystrophin associated proteins wererestored at the sarcolemma. Analysis of the inflammatory infiltrateindicated a reduction of cytotoxic T cells in the post-treatmentmuscle biopsies in the 2 higher dose cohorts.Conclusion: We demonstrate the potential of AVI-4658 to becomea disease modifying drug in the treatment of DMD.",
author = "Sebahattin Cirak and Virginia Arechavala-Gomeza and Michela Guglieri and Lucy Feng and Silvia Torelli and Karen Anthony and Garralda, {Maria Elena} and Wells, {Dominic J.} and George Dickson and Wood, {Matthew Ja} and Wilton, {Stephen D.} and Volker Straub and Shrewsbury, {Stephen B.} and Caroline Sewry and Jennifer Morgan and Kate Bushby and Francesco Muntoni",
year = "2011",
language = "English",
journal = "Neuromuscular Disorders",
issn = "0960-8966",
publisher = "Elsevier",

}

Cirak, S, Arechavala-Gomeza, V, Guglieri, M, Feng, L, Torelli, S, Anthony, K, Garralda, ME, Wells, DJ, Dickson, G, Wood, MJ, Wilton, SD, Straub, V, Shrewsbury, SB, Sewry, C, Morgan, J, Bushby, K & Muntoni, F 2011, 'Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment', Neuromuscular Disorders.

Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment. / Cirak, Sebahattin; Arechavala-Gomeza, Virginia; Guglieri, Michela; Feng, Lucy; Torelli, Silvia; Anthony, Karen; Garralda, Maria Elena; Wells, Dominic J.; Dickson, George; Wood, Matthew Ja; Wilton, Stephen D.; Straub, Volker; Shrewsbury, Stephen B.; Sewry, Caroline; Morgan, Jennifer; Bushby, Kate; Muntoni, Francesco.

In: Neuromuscular Disorders, 2011.

Research output: Contribution to journalAbstractResearchpeer-review

TY - JOUR

T1 - Exon skipping and dystrophin restoration in Duchenne muscular dystrophy patients after systemic phosphorodiamidate morpholino oligomer treatment

AU - Cirak, Sebahattin

AU - Arechavala-Gomeza, Virginia

AU - Guglieri, Michela

AU - Feng, Lucy

AU - Torelli, Silvia

AU - Anthony, Karen

AU - Garralda, Maria Elena

AU - Wells, Dominic J.

AU - Dickson, George

AU - Wood, Matthew Ja

AU - Wilton, Stephen D.

AU - Straub, Volker

AU - Shrewsbury, Stephen B.

AU - Sewry, Caroline

AU - Morgan, Jennifer

AU - Bushby, Kate

AU - Muntoni, Francesco

PY - 2011

Y1 - 2011

N2 - Objective: We report biochemical efficacy and clinical safety ofa phase 1b/2 dose-ranging study of IV administered AVI-4658,an antisense morpholino oligomer which restores the readingframe and enables dystrophin expression in Duchenne musculardystrophy (DMD) patients with amenable deletions for exon 51skipping.Method: AVI-4658 was given weekly for 12 weeks by intravenousinfusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. Theprimary study objective was safety and tolerability over the26 week study. Secondary objectives were: 1) pharmacokineticproperties, 2) ability of AVI-4658 to induce exon skipping anddystrophin expression by RT-PCR, immunohistochemistry andimmunoblotting.Results: AVI-4658 was well tolerated with no drug related seriousadverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658induced exon 51 skipping in the first 4 cohorts, followed byboth stronger skipping and dystrophin protein expression in agenerally dose dependent, but variable, manner in boys fromcohort 3 onwards. A total of 7 subjects displayed an increase ofdystrophin expression in the post-treatment biopsy, with 3 subjectsshowing a substantial increase in positive fibers (15%, 21% and55%, respectively). Additionally dystrophin associated proteins wererestored at the sarcolemma. Analysis of the inflammatory infiltrateindicated a reduction of cytotoxic T cells in the post-treatmentmuscle biopsies in the 2 higher dose cohorts.Conclusion: We demonstrate the potential of AVI-4658 to becomea disease modifying drug in the treatment of DMD.

AB - Objective: We report biochemical efficacy and clinical safety ofa phase 1b/2 dose-ranging study of IV administered AVI-4658,an antisense morpholino oligomer which restores the readingframe and enables dystrophin expression in Duchenne musculardystrophy (DMD) patients with amenable deletions for exon 51skipping.Method: AVI-4658 was given weekly for 12 weeks by intravenousinfusions in a dose escalation study (0.5, 1.0, 2.0, 4.0, 10 and20 mg/kg) to 19 ambulant DMD patients aged 5–15 years. Theprimary study objective was safety and tolerability over the26 week study. Secondary objectives were: 1) pharmacokineticproperties, 2) ability of AVI-4658 to induce exon skipping anddystrophin expression by RT-PCR, immunohistochemistry andimmunoblotting.Results: AVI-4658 was well tolerated with no drug related seriousadverse events. We compared dystrophin levels in pre- and posttreatment (two weeks after last dose) muscle biopsies. AVI-4658induced exon 51 skipping in the first 4 cohorts, followed byboth stronger skipping and dystrophin protein expression in agenerally dose dependent, but variable, manner in boys fromcohort 3 onwards. A total of 7 subjects displayed an increase ofdystrophin expression in the post-treatment biopsy, with 3 subjectsshowing a substantial increase in positive fibers (15%, 21% and55%, respectively). Additionally dystrophin associated proteins wererestored at the sarcolemma. Analysis of the inflammatory infiltrateindicated a reduction of cytotoxic T cells in the post-treatmentmuscle biopsies in the 2 higher dose cohorts.Conclusion: We demonstrate the potential of AVI-4658 to becomea disease modifying drug in the treatment of DMD.

M3 - Abstract

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

ER -