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.
UR - http://www.mendeley.com/research/exon-skipping-dystrophin-restoration-patients-duchenne-muscular-dystrophy-after-systemic-phosphorodi-3
U2 - 10.1016/S0140-6736(11)60756-3
DO - 10.1016/S0140-6736(11)60756-3
M3 - Article
C2 - 21784508
SN - 1474-547X
SP - 595
EP - 605
JO - The Lancet
JF - The Lancet
ER -