{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T15:23:54Z","timestamp":1777908234453,"version":"3.51.4"},"reference-count":50,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T00:00:00Z","timestamp":1643673600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["The CRISPR Journal"],"published-print":{"date-parts":[[2022,2,1]]},"abstract":"<jats:p>\n                    Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by mutations in the\n                    <jats:italic toggle=\"yes\">Arylsulfatase-A<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">ARSA<\/jats:italic>\n                    ) gene. The enzyme plays a key role in sulfatide metabolism in brain cells, and its deficiency leads to neurodegeneration. The clinical manifestations of MLD include stagnation and decline of motor and cognitive function, leading to premature death with limited standard treatment options. Here, we describe a mutation-agnostic hematopoietic stem and progenitor cell (HSPC) gene therapy using CRISPR-Cas9 and AAV6 repair template as a prospective treatment option for MLD. Our strategy achieved efficient insertions and deletions (&gt;87%) and a high level of gene integration (&gt;47%) at the\n                    <jats:italic toggle=\"yes\">ARSA<\/jats:italic>\n                    locus in human bone marrow\u2013derived HSPCs, with no detectable off-target editing. As a proof of concept, we tested our mutation-agnostic therapy in HSPCs derived from two MLD patients with distinct mutations and demonstrated restoration of ARSA enzyme activity (&gt;30-fold improvement) equivalent to healthy adults. In summary, our investigation enabled a mutation-agnostic therapy for MLD patients with proven efficacy and strong potential for clinical translation.\n                  <\/jats:p>","DOI":"10.1089\/crispr.2021.0075","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T10:33:19Z","timestamp":1639045999000},"page":"66-79","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["A Mutation-Agnostic Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy"],"prefix":"10.1177","volume":"5","author":[{"given":"Justin S.","family":"Antony","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Daniel-Moreno","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Lamsfus-Calle","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janani","family":"Raju","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merve","family":"Kaftancioglu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo","family":"Ure\u00f1a-Bail\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Rottenberger","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujuan","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vidiyaah","family":"Santhanakumaran","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, University Children's Hospital T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Hoe","family":"Lee","sequence":"additional","affiliation":[{"name":"Quantitative Biology Center (QBiC), University of T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas","family":"Heumos","sequence":"additional","affiliation":[{"name":"Quantitative Biology Center (QBiC), University of T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"B\u00f6hringer","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"},{"name":"Department of Pediatric Neurology, University Children's Hospital T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingeborg","family":"Kr\u00e4geloh-Mann","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, University Children's Hospital T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rupert","family":"Handgretinger","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Mezger","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Children's Hospital, University of T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2014.10.001"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011047"},{"key":"e_1_3_5_4_2","volume-title":"Metachromatic Leukodystrophy","author":"Gieselmann Volkmar IK","year":"2014","unstructured":"Gieselmann Volkmar IK. 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