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<title>CSF-directed AAV9 gene therapy plus subcutaneous copper provides superior rescue in a mouse model of Menkes disease | NIH Research Festival</title>
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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>CSF-directed AAV9 gene therapy plus subcutaneous copper provides superior rescue in a mouse model of Menkes disease</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session V
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">2:00 – 3:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NICHD</strong></p></div><div class="schedule__description"><p><strong>NEURO-14</strong></p></div></div></div></div><p><strong>FARE Award Winner</strong></p><h2>Authors</h2><ul><li>MR Haddad</li><li>D Martinelli</li><li>EY Choi</li><li>PM Zerfas</li><li>P Sullivan</li><li>DS Goldstein</li><li>D Abebe</li><li>JA Centeno</li><li>SG Kaler</li></ul><h2>Abstract</h2><p>Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase ATP7A. Untreated patients die by 3 years. Currently, the only available treatment is daily subcutaneous copper-histidine injections, which is not effective in the majority of patients who would benefit from gene therapy. The mottled-brindled mouse recapitulates the Menkes phenotype and the mutants die by 14 days of age. We used Adeno-Associated Virus (AAV) vectors carrying ATP7A cDNA. We previously demonstrated that AAV serotype 5 (AAV5) in combination with copper both given into the brain’s lateral ventricles (ICV) was able to significantly prolong the survival of the mutants. However, subtle abnormalities in growth and neuromotor functions persisted. In this study, we report far superior outcomes using AAV9 given ICV in combination with subcutaneous copper-histidine. We employed AAV9 and AAVrh10 given their broad tropism compared to AAV5. We used 3 different doses: high (1.6x1010vg), intermediate (5.0x109vg) and low (1.6x109vg) plus copper; our intermediate and high AAV9-ATP7A doses were most effective. Cerebrospinal fluid-directed AAV9 with subcutaneous Cu resulted in superior murine survival, neurobehavioral outcomes and growth compared to AAVrh10 and to our previous results with AAV5. In addition, this synergistic effect (high AAV9+Cu) showed improved brain neurochemicals compared to untreated and correlated with viral genome copies. Copper measurements in combination-treated mutants were not statistically different from wild type suggesting a restored copper transport to the brain. Our findings provide definitive evidence that gene therapy has clinical utility in the treatment of Menkes disease.</p><p><strong>Scientific Focus Area</strong>: Neuroscience</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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