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.
BACKGROUND: 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. METHOD: We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1826264266768908288 |
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| author | Cirak, S Arechavala-Gomeza, V Guglieri, M Feng, L Torelli, S Anthony, K Abbs, S Garralda, M Bourke, J Wells, D Dickson, G Wood, M Wilton, S Straub, V Kole, R Shrewsbury, S Sewry, C Morgan, J Bushby, K Muntoni, F |
| author_facet | Cirak, S Arechavala-Gomeza, V Guglieri, M Feng, L Torelli, S Anthony, K Abbs, S Garralda, M Bourke, J Wells, D Dickson, G Wood, M Wilton, S Straub, V Kole, R Shrewsbury, S Sewry, C Morgan, J Bushby, K Muntoni, F |
| author_sort | Cirak, S |
| collection | OXFORD |
| description | BACKGROUND: 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. METHOD: 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. FINDINGS: 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. INTERPRETATION: The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. FUNDING: UK Medical Research Council; AVI BioPharma. |
| first_indexed | 2024-03-06T20:05:00Z |
| format | Journal article |
| id | oxford-uuid:289d43f4-dcf3-4d60-abce-d3e1209eeb89 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:05:00Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:289d43f4-dcf3-4d60-abce-d3e1209eeb892022-03-26T12:14:02ZExon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:289d43f4-dcf3-4d60-abce-d3e1209eeb89EnglishSymplectic Elements at Oxford2011Cirak, SArechavala-Gomeza, VGuglieri, MFeng, LTorelli, SAnthony, KAbbs, SGarralda, MBourke, JWells, DDickson, GWood, MWilton, SStraub, VKole, RShrewsbury, SSewry, CMorgan, JBushby, KMuntoni, FBACKGROUND: 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. METHOD: 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. FINDINGS: 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. INTERPRETATION: The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. FUNDING: UK Medical Research Council; AVI BioPharma. |
| spellingShingle | Cirak, S Arechavala-Gomeza, V Guglieri, M Feng, L Torelli, S Anthony, K Abbs, S Garralda, M Bourke, J Wells, D Dickson, G Wood, M Wilton, S Straub, V Kole, R Shrewsbury, S Sewry, C Morgan, J Bushby, K Muntoni, F 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. |
| title | 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
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