Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study

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

Research output: Contribution to JournalArticle

Abstract

We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9 (95 CI 7·1-10·6) to 16·4 (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21, 15, and 55 dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2 to 18, from 0·9 to 17, and from 0 to 7·7 of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. UK Medical Research Council; AVI BioPharma. © 2011 Elsevier Ltd.
Original languageEnglish
Pages (from-to)595-605
Number of pages11
JournalThe Lancet
DOIs
Publication statusPublished - 13 Aug 2011

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Morpholinos
Dystrophin
Duchenne Muscular Dystrophy
Exons
Safety
Muscles
Therapeutics
Dystrophin-Associated Proteins
Sarcoglycans
Biopsy
Sarcolemma
Nitric Oxide Synthase Type I
AVI-4658
Immunoblotting
Intravenous Infusions
Pharmaceutical Preparations
Biomedical Research
Proteins
Pharmacokinetics
Fluorescence

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Cirak, Sebahattin ; Arechavala-Gomeza, Virginia ; Guglieri, Michela ; Feng, Lucy ; Torelli, Silvia ; Anthony, Karen ; Abbs, Stephen ; Garralda, Maria Elena ; Bourke, John ; Wells, Dominic J. ; Dickson, George ; Wood, Matthew Ja ; Wilton, Steve D. ; Straub, Volker ; Kole, Ryszard ; Shrewsbury, Stephen B. ; Sewry, Caroline ; Morgan, Jennifer E. ; Bushby, Kate ; Muntoni, Francesco. / Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. In: The Lancet. 2011 ; pp. 595-605.
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abstract = "We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9 (95 CI 7·1-10·6) to 16·4 (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21, 15, and 55 dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2 to 18, from 0·9 to 17, and from 0 to 7·7 of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. UK Medical Research Council; AVI BioPharma. {\circledC} 2011 Elsevier Ltd.",
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Cirak, S, Arechavala-Gomeza, V, Guglieri, M, Feng, L, Torelli, S, Anthony, K, Abbs, S, Garralda, ME, Bourke, J, Wells, DJ, Dickson, G, Wood, MJ, Wilton, SD, Straub, V, Kole, R, Shrewsbury, SB, Sewry, C, Morgan, JE, Bushby, K & Muntoni, F 2011, 'Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study', The Lancet, pp. 595-605. https://doi.org/10.1016/S0140-6736(11)60756-3

Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. / Cirak, Sebahattin; Arechavala-Gomeza, Virginia; Guglieri, Michela; Feng, Lucy; Torelli, Silvia; Anthony, Karen; Abbs, Stephen; Garralda, Maria Elena; Bourke, John; Wells, Dominic J.; Dickson, George; Wood, Matthew Ja; Wilton, Steve D.; Straub, Volker; Kole, Ryszard; Shrewsbury, Stephen B.; Sewry, Caroline; Morgan, Jennifer E.; Bushby, Kate; Muntoni, Francesco.

In: The Lancet, 13.08.2011, p. 595-605.

Research output: Contribution to JournalArticle

TY - JOUR

T1 - Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study

AU - Cirak, Sebahattin

AU - Arechavala-Gomeza, Virginia

AU - Guglieri, Michela

AU - Feng, Lucy

AU - Torelli, Silvia

AU - Anthony, Karen

AU - Abbs, Stephen

AU - Garralda, Maria Elena

AU - Bourke, John

AU - Wells, Dominic J.

AU - Dickson, George

AU - Wood, Matthew Ja

AU - Wilton, Steve D.

AU - Straub, Volker

AU - Kole, Ryszard

AU - Shrewsbury, Stephen B.

AU - Sewry, Caroline

AU - Morgan, Jennifer E.

AU - Bushby, Kate

AU - Muntoni, Francesco

PY - 2011/8/13

Y1 - 2011/8/13

N2 - We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9 (95 CI 7·1-10·6) to 16·4 (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21, 15, and 55 dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2 to 18, from 0·9 to 17, and from 0 to 7·7 of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. UK Medical Research Council; AVI BioPharma. © 2011 Elsevier Ltd.

AB - We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5-15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9 (95 CI 7·1-10·6) to 16·4 (10·8-22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21, 15, and 55 dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2 to 18, from 0·9 to 17, and from 0 to 7·7 of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. UK Medical Research Council; AVI BioPharma. © 2011 Elsevier Ltd.

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