{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:45:46Z","timestamp":1789764346366,"version":"4.0.1"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mayo Foundation Education Fund"},{"name":"Legacy of Angels Foundation"},{"name":"MidAtlantic Neonatology Associates"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Krabbe disease (KD) is a progressive and devasting neurological disorder that leads to the toxic accumulation of psychosine in the white matter of the central nervous system (CNS). The condition is inherited via biallelic, loss-of-function mutations in the galactosylceramidase (GALC) gene. To rescue GALC gene function in the CNS of the twitcher mouse model of KD, an adeno-associated virus serotype 1 vector expressing murine GALC under control of a chicken \u03b2-actin promoter (AAV1-GALC) was administered to newborn mice by unilateral intracerebroventricular injection. AAV1-GALC treatment significantly improved body weight gain and survival of the twitcher mice (n = 8) when compared with untreated controls (n = 5). The maximum weight gain after postnatal day 10 was significantly increased from 81% to 217%. The median lifespan was extended from 43 days to 78 days (range: 74\u201388 days) in the AAV1-GALC-treated group. Widespread expression of GALC protein and alleviation of KD neuropathology were detected in the CNS of the treated mice when examined at the moribund stage. Functionally, elevated levels of psychosine were completely normalized in the forebrain region of the treated mice. In the posterior region, which includes the mid- and the hindbrain, psychosine was reduced by an average of 77% (range: 53\u201393%) compared to the controls. Notably, psychosine levels in this region were inversely correlated with body weight and lifespan of AAV1-GALC-treated mice, suggesting that the degree of viral transduction of posterior brain regions following ventricular injection determined treatment efficacy on growth and survivability, respectively. Overall, our results suggest that viral vector delivery via the cerebroventricular system can partially correct psychosine accumulation in brain that leads to slower disease progression in KD.<\/jats:p>","DOI":"10.3390\/genes14081517","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:45:02Z","timestamp":1690332302000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Brain Targeted AAV1-GALC Gene Therapy Reduces Psychosine and Extends Lifespan in a Mouse Model of Krabbe Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Aimee R.","family":"Herdt","sequence":"first","affiliation":[{"name":"Biomedical Research Institute of New Jersey, Cedar Knolls, NJ 07927, USA"},{"name":"MidAtlantic Neonatology Associates (MANA), Morristown, NJ 07960, USA"},{"name":"Atlantic Health System, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Peng","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute of New Jersey, Cedar Knolls, NJ 07927, USA"},{"name":"MidAtlantic Neonatology Associates (MANA), Morristown, NJ 07960, USA"},{"name":"Atlantic Health System, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1867-7071","authenticated-orcid":false,"given":"Todd E.","family":"Golde","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Neurology, Emory University, Atlanta, GA 30322, USA"},{"name":"Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5391-4960","authenticated-orcid":false,"given":"Elizabeth A.","family":"Eckman","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute of New Jersey, Cedar Knolls, NJ 07927, USA"},{"name":"MidAtlantic Neonatology Associates (MANA), Morristown, NJ 07960, USA"},{"name":"Atlantic Health System, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9068-5274","authenticated-orcid":false,"given":"Chris W.","family":"Lee","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute of New Jersey, Cedar Knolls, NJ 07927, USA"},{"name":"MidAtlantic Neonatology Associates (MANA), Morristown, NJ 07960, USA"},{"name":"Atlantic Health System, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/B978-0-444-59565-2.00029-0","article-title":"Lysosomal leukodystrophies: Krabbe disease and metachromatic leukodystrophy","volume":"113","author":"Kohlschutter","year":"2013","journal-title":"Handb. 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