{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:19:44Z","timestamp":1785435584327,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,10]]},"group-title":"Pathology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01-DK36425"],"award-info":[{"award-number":["R01-DK36425"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01-AR085061"],"award-info":[{"award-number":["R01-AR085061"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"SEAL Therapeutics","award":["no number"],"award-info":[{"award-number":["no number"]}]},{"name":"Rutgers Health Bridge Funding","award":["no number"],"award-info":[{"award-number":["no number"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The\n                  <jats:italic>\n                    dy\n                    <jats:sup>3K<\/jats:sup>\n                    \/dy\n                    <jats:sup>3K<\/jats:sup>\n                  <\/jats:italic>\n                  Lama2\n                  <jats:bold>\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:bold>\n                  mouse is a model for the severe form of LAMA2-related dystrophy and peripheral neuropathy (LAMA2-RD). In the dystrophic mice, a compensating laminin subunit, Lm\u03b14, that lacks polymerization and \u03b1-dystroglycan-binding activity, replaces the missing Lm\u03b12 subunit. It was previously found that an \u03b14-laminin can be modified with two small laminin-binding linker proteins, i.e. \u03b1LNNd\u0394G2\u2019 and miniagrin to facilitate polymerization and \u03b1-dystroglycan binding respectively, to enable the key missing functions. Adeno-associated virus serotype 9 (AAV\n                  <jats:sub>9<\/jats:sub>\n                  ) was used to deliver minigenes coding for the two proteins in dystrophic mice. AAV\n                  <jats:sub>9<\/jats:sub>\n                  -\u03b1LNNd\u0394G2\u2019 utilized a universal CBh promoter while AAV\n                  <jats:sub>9<\/jats:sub>\n                  -miniagrin utilized either the CBh promoter or muscle-specific SPc5-12 promoter. The phenotype in the\n                  <jats:italic>\n                    dy\n                    <jats:sup>3K<\/jats:sup>\n                    \/dy\n                    <jats:sup>3K<\/jats:sup>\n                  <\/jats:italic>\n                  mice was evaluated following i.v. postnatal injection with either AAV\n                  <jats:sub>9<\/jats:sub>\n                  -\u03b1LNNd\u0394G2\u2019 alone or in combination with AAV\n                  <jats:sub>9<\/jats:sub>\n                  - \u03b1LNNd\u0394G2\u2019 + AAV\n                  <jats:sub>9-<\/jats:sub>\n                  miniagrin. Double AAV treatment was found to substantially increase survival and ambulation, as well as increase forelimb grip-strength and improve muscle histology. Of note, the sciatic nerve amyelination characteristic of laminin \u03b12-deficiency was prevented. While single treatment with \u03b1LNNd\u0394G2\u2019 was inferior to double treatment for muscle strength and survival, it corrected the radial sorting deficit equally, revealing that enablement of laminin polymerization is a sufficient requirement for myelination.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        The\n                        <jats:italic>\n                          dy\n                          <jats:sup>3K<\/jats:sup>\n                          \/dy\n                          <jats:sup>3K<\/jats:sup>\n                        <\/jats:italic>\n                        (Lama2\n                        <jats:sup>-\/-<\/jats:sup>\n                        ) mouse, a model for severe LAMA2-related dystrophy, expresses laminin-411 that is unable to polymerize or bind to \u03b1-dystroglycan (\u03b1DG).\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\u03b1LNNd\u0394G2\u2019 and miniagrin are laminin-411-binding proteins that enable polymerization and \u03b1DG binding.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        AAV\n                        <jats:sub>9<\/jats:sub>\n                        delivery of genes coding for \u03b1LNNd\u0394G2\u2019 and miniagrin ameliorated the dystrophic phenotype in muscle and nerve (survival, growth, mobility, and grip-strength, muscle and nerve histopathology).\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Sciatic nerve amyelination was prevented by \u03b1LNNd\u0394G2\u2019 alone.<\/jats:p>\n                    <\/jats:list-item>\n     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