A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy
<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that ca...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2007-09-01
|
Series: | Journal of Translational Medicine |
Online Access: | http://www.translational-medicine.com/content/5/1/45 |
id |
doaj-407102c4dd634c71bb3f4b11689bfa5c |
---|---|
record_format |
Article |
spelling |
doaj-407102c4dd634c71bb3f4b11689bfa5c2020-11-24T22:05:00ZengBMCJournal of Translational Medicine1479-58762007-09-01514510.1186/1479-5876-5-45A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophyChicoine Louis GColey Brian DMontgomery Chrystal LJanssen Paul MLRodino-Klapac Louise RClark K ReedMendell Jerry R<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.</p> <p>Methods</p> <p>The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the N-terminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL). The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD.</p> <p>Results</p> <p>Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month), 91.3 ± 3.1 (2 months), and 89.6 ± 1.6% (3 months). rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month), 78.9 ± 7.4 (2 months), and 81.2 ± 6.2% (3 months) transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month), 2.1 ± 0.8 (2 months), and 2.1 ± 0.7% (3 months)] by vascular delivery. Micro-dystrophin delivered by rAAV8 and rAAV6 through the femoral artery significantly improved tetanic force and protected against eccentric contraction. Mouse studies translated to the hindlimb of cynamologous macaques using a similar vascular delivery paradigm. rAAV8 carrying eGFP in doses proportional to the mouse (5 × 10<sup>12 </sup>vg/kg in mouse vs 2 × 10<sup>12 </sup>vg/kg in monkey) demonstrated widespread gene expression [medial gastrocnemius – 63.8 ± 4.9%, lateral gastrocnemius – 66.0 ± 4.5%, EDL – 80.2 ± 3.1%, soleus – 86.4 ± 1.9%, TA – 72.2 ± 4.0%.</p> <p>Conclusion</p> <p>These studies demonstrate regional vascular gene delivery with AAV serotype(s) in mouse and non-human primate at doses, pressures and volumes applicable for clinical trials in children with DMD.</p> http://www.translational-medicine.com/content/5/1/45 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chicoine Louis G Coley Brian D Montgomery Chrystal L Janssen Paul ML Rodino-Klapac Louise R Clark K Reed Mendell Jerry R |
spellingShingle |
Chicoine Louis G Coley Brian D Montgomery Chrystal L Janssen Paul ML Rodino-Klapac Louise R Clark K Reed Mendell Jerry R A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy Journal of Translational Medicine |
author_facet |
Chicoine Louis G Coley Brian D Montgomery Chrystal L Janssen Paul ML Rodino-Klapac Louise R Clark K Reed Mendell Jerry R |
author_sort |
Chicoine Louis G |
title |
A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy |
title_short |
A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy |
title_full |
A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy |
title_fullStr |
A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy |
title_full_unstemmed |
A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy |
title_sort |
translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of duchenne muscular dystrophy |
publisher |
BMC |
series |
Journal of Translational Medicine |
issn |
1479-5876 |
publishDate |
2007-09-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.</p> <p>Methods</p> <p>The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the N-terminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL). The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD.</p> <p>Results</p> <p>Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month), 91.3 ± 3.1 (2 months), and 89.6 ± 1.6% (3 months). rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month), 78.9 ± 7.4 (2 months), and 81.2 ± 6.2% (3 months) transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month), 2.1 ± 0.8 (2 months), and 2.1 ± 0.7% (3 months)] by vascular delivery. Micro-dystrophin delivered by rAAV8 and rAAV6 through the femoral artery significantly improved tetanic force and protected against eccentric contraction. Mouse studies translated to the hindlimb of cynamologous macaques using a similar vascular delivery paradigm. rAAV8 carrying eGFP in doses proportional to the mouse (5 × 10<sup>12 </sup>vg/kg in mouse vs 2 × 10<sup>12 </sup>vg/kg in monkey) demonstrated widespread gene expression [medial gastrocnemius – 63.8 ± 4.9%, lateral gastrocnemius – 66.0 ± 4.5%, EDL – 80.2 ± 3.1%, soleus – 86.4 ± 1.9%, TA – 72.2 ± 4.0%.</p> <p>Conclusion</p> <p>These studies demonstrate regional vascular gene delivery with AAV serotype(s) in mouse and non-human primate at doses, pressures and volumes applicable for clinical trials in children with DMD.</p> |
url |
http://www.translational-medicine.com/content/5/1/45 |
work_keys_str_mv |
AT chicoinelouisg atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT coleybriand atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT montgomerychrystall atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT janssenpaulml atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT rodinoklapaclouiser atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT clarkkreed atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT mendelljerryr atranslationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT chicoinelouisg translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT coleybriand translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT montgomerychrystall translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT janssenpaulml translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT rodinoklapaclouiser translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT clarkkreed translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy AT mendelljerryr translationalapproachforlimbvasculardeliveryofthemicrodystrophingenewithouthighvolumeorhighpressurefortreatmentofduchennemusculardystrophy |
_version_ |
1725827744244170752 |