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These diseases exhibit diverse pathophysiological processes and are a topic of intense experimental and clinical research due to the lack of therapeutic options. Restorative therapies are promising approaches with the potential to restore brain circuits. However, there were less compelling results in the few clinical trials. In this review, we discuss cell replacement therapies applied to animal models and HD patients. We thoroughly describe the initial trials using fetal neural tissue transplantation and recent approaches based on alternative cell sources tested in several animal models. Stem cells were shown to generate the desired neuron phenotype and\/or provide growth factors to the degenerating host cells. Besides, genetic approaches such as RNA interference and the CRISPR\/Cas9 system have been studied in animal models and human\u2010derived cells. New genetic manipulations have revealed the capability to control or counteract the effect of human gene mutations as described by the use of antisense oligonucleotides in a clinical trial. In HD, innovative strategies are at forefront of human testing and thus other brain genetic diseases may follow similar therapeutic strategies.<\/jats:p>","DOI":"10.1002\/jnr.24845","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T22:08:05Z","timestamp":1619042885000},"page":"1744-1762","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Revisiting cell and gene therapies in Huntington\u2019s disease"],"prefix":"10.1002","volume":"99","author":[{"given":"Margarida","family":"Beatriz","sequence":"first","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra \u2013 Polo I Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Lopes","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra \u2013 Polo I Coimbra Portugal"},{"name":"IIIUC\u2010Institute for Interdisciplinary Research University of Coimbra \u2013 Polo II Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cl\u00e1udia S.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"FMUC\u2010Faculty of Medicine University of Coimbra \u2013 Polo III Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina Carvalho","family":"Rego","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology University of Coimbra \u2013 Polo I Coimbra Portugal"},{"name":"FMUC\u2010Faculty of Medicine University of Coimbra \u2013 Polo III Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.04.026"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808488105"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1999.7239"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(06)70381-7"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2012-302441"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.17"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.12.042"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.02.035"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.084608"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-019-0066-7"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2004.08.015"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24174"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx255"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1715865115"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00075"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(94)90526-6"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-013-9441-8"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2010.05.023"},{"key":"e_1_2_11_20_1","first-page":"213","volume-title":"Methods of behavior analysis in neuroscience","author":"Dobrossy M. 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