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Currently, there are no therapies that target axons to prevent them from degenerating. Activation of the BAX protein has been shown to be the determining step in the intrinsic apoptotic pathway that causes RGCs to die in glaucoma. A putative role for BAX in axonal degeneration is less well elucidated. BCLX<jats:sub>L<\/jats:sub> (BCL2L1) is the primary antagonist of BAX in RGCs. We developed a mCherry-BCLX<jats:sub>L<\/jats:sub> fusion protein, which prevented BAX recruitment and activation to the mitochondria in tissue culture cells exposed to staurosporine. This fusion protein was then packaged into adeno-associated virus serotype 2, which was used to transduce RGCs after intravitreal injection and force its overexpression. Transduced RGCs express mCherry-BCLX<jats:sub>L<\/jats:sub> throughout their somas and axons along the entire optic tract. In a model of acute optic nerve crush, the transgene prevented the recruitment of a GFP-BAX fusion protein to mitochondria and provided long-term somal protection up to 12 weeks post injury. To test the efficacy in glaucoma, DBA\/2J mice were transduced at 5 months of age, just prior to the time they begin to exhibit ocular hypertension. Gene therapy with mCherry-BCLX<jats:sub>L<\/jats:sub> did not affect the longitudinal history of intraocular pressure elevation compared to naive mice but did robustly attenuate both RGC soma pathology and axonal degeneration in the optic nerve at both 10.5 and 12 months of age. BCLX<jats:sub>L<\/jats:sub> gene therapy is a promising candidate for glaucoma therapy.<\/jats:p>","DOI":"10.1038\/s41419-021-04068-x","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T07:04:12Z","timestamp":1628579052000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["BCLXL gene therapy moderates neuropathology in the DBA\/2J mouse model of inherited glaucoma"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2519-0763","authenticated-orcid":false,"given":"Ryan J.","family":"Donahue","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2999-6281","authenticated-orcid":false,"given":"Rachel L.","family":"Fehrman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1689-9749","authenticated-orcid":false,"given":"Jenna R.","family":"Gustafson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2998-5494","authenticated-orcid":false,"given":"Robert W.","family":"Nickells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"4068_CR1","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/S0140-6736(10)61423-7","volume":"377","author":"HA Quigley","year":"2011","unstructured":"Quigley HA. 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