SLC26A4 encodes pendrin, a crucial anion exchanger essential for maintaining hearing function. Mutations in SLC26A4, including the prevalent c.919-2 A > G splice-site mutation among East Asian individuals, can disrupt inner ear electrolyte balance, leading to syndromic and non-syndromic hearing loss, such as Pendred syndrome and DFNB4. To explore potential therapeutic strategies, we utilized CRISPR/Cas9-mediated exon skipping to create a Slc26a4∆E8+E9/∆E8+E9 mouse model. We assessed pendrin expression in the inner ear and evaluated vestibular and auditory functions. The Slc26a4∆E8+E9/∆E8+E9 mice demonstrated reframed pendrin in the inner ear and normal vestibular functions, contrasting with severely abnormal vestibular functions observed in the Slc26a4 c.919-2 A > G splicing mutation mouse model. However, despite these molecular achievements, hearing function did not show the expected improvement, consistent with observed pathology, including cochlear hair cell loss and elevated hearing thresholds. Consequently, our findings highlight the necessity for alternative genetic editing strategies to address hearing loss caused by the SLC26A4 c.919-2 A > G mutation.
SLC26A4 编码pendrin，这是一种对维持听力功能至关重要的阴离子交换剂。SLC26A4 的突变，包括东亚人中普遍存在的 c.919-2 A > G 拼接位点突变，会破坏内耳电解质平衡，导致综合征和非综合征性听力损失，如 Pendred 综合征和 DFNB4。为了探索潜在的治疗策略，我们利用 CRISPR/Cas9 介导的外显子跳过技术创建了 Slc26a4∆E8+E9/∆E8+E9 小鼠模型。我们评估了pendrin在内耳中的表达，并评估了前庭和听觉功能。Slc26a4ΔE8+E9/ΔE8+E9小鼠的内耳中重构了pendrin，前庭功能正常，这与Slc26a4 c.919-2 A > G剪接突变小鼠模型中观察到的前庭功能严重异常形成了鲜明对比。然而，尽管取得了这些分子成就，听觉功能并没有出现预期的改善，这与观察到的病理变化一致，包括耳蜗毛细胞缺失和听阈升高。因此，我们的研究结果突出表明，有必要采用替代基因编辑策略来解决 SLC26A4 c.919-2 A > G 突变导致的听力损失问题。
{"title":"CRISPR/Cas9-mediated exon skipping to restore premature translation termination in a DFNB4 mouse model","authors":"Chun-Ying Huang, Yi-Hsiu Tsai, Yi-Fen Cheng, Peng-Yu Wu, Yu-Chi Chuang, Po-Yuan Huang, Jai-Shin Liu, Chen-Chi Wu, Yen-Fu Cheng","doi":"10.1038/s41434-024-00483-9","DOIUrl":"10.1038/s41434-024-00483-9","url":null,"abstract":"SLC26A4 encodes pendrin, a crucial anion exchanger essential for maintaining hearing function. Mutations in SLC26A4, including the prevalent c.919-2 A > G splice-site mutation among East Asian individuals, can disrupt inner ear electrolyte balance, leading to syndromic and non-syndromic hearing loss, such as Pendred syndrome and DFNB4. To explore potential therapeutic strategies, we utilized CRISPR/Cas9-mediated exon skipping to create a Slc26a4∆E8+E9/∆E8+E9 mouse model. We assessed pendrin expression in the inner ear and evaluated vestibular and auditory functions. The Slc26a4∆E8+E9/∆E8+E9 mice demonstrated reframed pendrin in the inner ear and normal vestibular functions, contrasting with severely abnormal vestibular functions observed in the Slc26a4 c.919-2 A > G splicing mutation mouse model. However, despite these molecular achievements, hearing function did not show the expected improvement, consistent with observed pathology, including cochlear hair cell loss and elevated hearing thresholds. Consequently, our findings highlight the necessity for alternative genetic editing strategies to address hearing loss caused by the SLC26A4 c.919-2 A > G mutation.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"531-540"},"PeriodicalIF":4.6,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00483-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study assessed the relationship between NGF expression in the bladder and bladder hypersensitivity caused by psychological stress using water avoidance stress (WAS) in rats by modulating the NGF expression using intravesical liposome-complexed NGF antisense oligonucleotide (OND) therapy on WAS-induced bladder dysfunction. Female Wistar rats were divided into control and WAS groups, the latter of which received WAS sessions for 10 days with or without the OND pretreatment. Rats underwent cystometry with or without intravesical application of low-dose protamine sulfate (LD-PS), or pain behavior measurements after LD-PS application. After functional evaluations, the bladder was harvested for histology and molecular studies. WAS rats with or without LD-PS showed shortened intercontraction intervals and increased pain behaviors compared to control rats, which was improved by OND-treatment. Histological studies revealed that LD-PS provoked urothelial exfoliation in WAS rats. Compared to controls, protein assay showed increased NGF levels, and RT-PCR showed increases of TRPV1 and TRPA1 and a decrease in Cx43 in WAS rat bladders, which were improved by OND-treatment. WAS caused bladder hypersensitivity, which was improved by NGF antisense OND treatment. NGF upregulation in the bladder may be a therapeutic target for the treatment of psychological stress-induced bladder dysfunction.
本研究通过膀胱内脂质体复合物NGF反义寡核苷酸（OND）治疗WAS诱导的膀胱功能障碍，评估膀胱中NGF的表达与大鼠因避水应激（WAS）引起的心理应激导致的膀胱超敏反应之间的关系。雌性 Wistar 大鼠分为对照组和 WAS 组，对照组接受为期 10 天的 WAS 治疗，无论是否进行了 OND 预处理。大鼠在膀胱内应用或不应用低剂量硫酸原胺（LD-PS）的情况下进行膀胱测量，或在应用 LD-PS 后进行疼痛行为测量。进行功能评估后，采集膀胱进行组织学和分子研究。与对照组大鼠相比，施用或未施用 LD-PS 的 WAS 大鼠的收缩间期缩短，疼痛行为增加，而OND 治疗可改善这种情况。组织学研究显示，LD-PS 会导致 WAS 大鼠的尿道脱落。与对照组相比，蛋白质检测显示 NGF 水平升高，RT-PCR 显示 WAS 大鼠膀胱中 TRPV1 和 TRPA1 水平升高，Cx43 水平降低，OND 治疗可改善这些情况。WAS 会导致膀胱超敏反应，而 NGF 反义OND 治疗可改善这种超敏反应。膀胱中NGF的上调可能是治疗心理压力引起的膀胱功能障碍的一个治疗靶点。
{"title":"Intravesical nerve growth factor antisense therapy for bladder hypersensitivity induced by psychological stress","authors":"Tetsuichi Saito, Pradeep Tyagi, Tomonori Minagawa, Teruyuki Ogawa, Osamu Ishizuka, Naoki Yoshimura","doi":"10.1038/s41434-024-00484-8","DOIUrl":"10.1038/s41434-024-00484-8","url":null,"abstract":"This study assessed the relationship between NGF expression in the bladder and bladder hypersensitivity caused by psychological stress using water avoidance stress (WAS) in rats by modulating the NGF expression using intravesical liposome-complexed NGF antisense oligonucleotide (OND) therapy on WAS-induced bladder dysfunction. Female Wistar rats were divided into control and WAS groups, the latter of which received WAS sessions for 10 days with or without the OND pretreatment. Rats underwent cystometry with or without intravesical application of low-dose protamine sulfate (LD-PS), or pain behavior measurements after LD-PS application. After functional evaluations, the bladder was harvested for histology and molecular studies. WAS rats with or without LD-PS showed shortened intercontraction intervals and increased pain behaviors compared to control rats, which was improved by OND-treatment. Histological studies revealed that LD-PS provoked urothelial exfoliation in WAS rats. Compared to controls, protein assay showed increased NGF levels, and RT-PCR showed increases of TRPV1 and TRPA1 and a decrease in Cx43 in WAS rat bladders, which were improved by OND-treatment. WAS caused bladder hypersensitivity, which was improved by NGF antisense OND treatment. NGF upregulation in the bladder may be a therapeutic target for the treatment of psychological stress-induced bladder dysfunction.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"607-613"},"PeriodicalIF":4.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1038/s41434-024-00481-x
Henna Korpela, Jaakko Lampela, Jonna Airaksinen, Niko Järveläinen, Satu Siimes, Kaisa Valli, Tiina Nieminen, Minttu Turunen, Maria Grönman, Antti Saraste, Juhani Knuuti, Mikko Hakulinen, Pekka Poutiainen, Vesa Kärjä, Jussi Nurro, Seppo Ylä-Herttuala
{"title":"Correction: AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses","authors":"Henna Korpela, Jaakko Lampela, Jonna Airaksinen, Niko Järveläinen, Satu Siimes, Kaisa Valli, Tiina Nieminen, Minttu Turunen, Maria Grönman, Antti Saraste, Juhani Knuuti, Mikko Hakulinen, Pekka Poutiainen, Vesa Kärjä, Jussi Nurro, Seppo Ylä-Herttuala","doi":"10.1038/s41434-024-00481-x","DOIUrl":"10.1038/s41434-024-00481-x","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"626-628"},"PeriodicalIF":4.6,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00481-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-25DOI: 10.1038/s41434-024-00480-y
Alexandra McCarron, Kak-Ming Ling, Samuel T. Montgomery, Kelly M. Martinovich, Patricia Cmielewski, Nathan Rout-Pitt, Anthony Kicic, David Parsons, Martin Donnelley
Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.
气道基因疗法等突变识别疗法有可能治疗任何囊性纤维化（CF）患者，无论其CF跨膜传导调节器（CFTR）基因变异情况如何。本研究的目的是利用两种CF大鼠模型（Phe508del和CFTR基因敲除（KO））来评估CFTR调节剂和慢病毒（LV）载体介导的基因疗法的比较效果。从大鼠气管中分离出细胞，用于建立气液界面（ALI）培养物。用调节剂组合 elexacaftor-tezacaftor-ivacaftor (ETI) 处理 Phe508del 大鼠 ALI，用 LV-CFTR 处理不同组的 Phe508del 和 KO 气管上皮细胞，然后在 ALI 上进行分化。进行乌星室测量以评估 CFTR 功能。经 ETI 处理的 Phe508del ALI 培养物的 CFTR 功能仅为野生型的 59%，而经基因添加疗法处理的 Phe508del 和 KO 细胞的 CFTR 功能分别恢复到野生型的 68% 和 47%。我们的研究结果表明，大鼠 Phe508del-CFTR 蛋白可通过 ETI 治疗成功挽救，而 CFTR 基因添加疗法可显著纠正 Phe508del 和 KO ALI 培养物中的 CFTR，使其达到与 ETI 相当的水平。这些发现凸显了基于 LV 载体的基因疗法治疗 CF 肺病的潜力。
{"title":"Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models","authors":"Alexandra McCarron, Kak-Ming Ling, Samuel T. Montgomery, Kelly M. Martinovich, Patricia Cmielewski, Nathan Rout-Pitt, Anthony Kicic, David Parsons, Martin Donnelley","doi":"10.1038/s41434-024-00480-y","DOIUrl":"10.1038/s41434-024-00480-y","url":null,"abstract":"Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"553-559"},"PeriodicalIF":4.6,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00480-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1038/s41434-024-00478-6
F. Sarinella, A. Calistri, P. Sette, G. Palù, C. Parolin
{"title":"Retraction Note: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway","authors":"F. Sarinella, A. Calistri, P. Sette, G. Palù, C. Parolin","doi":"10.1038/s41434-024-00478-6","DOIUrl":"10.1038/s41434-024-00478-6","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"530-530"},"PeriodicalIF":4.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00478-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1038/s41434-024-00473-x
Luca Giordano, Manish K. Aneja, Natascha Sommer, Nasim Alebrahimdehkordi, Alireza Seraji, Norbert Weissmann, Carsten Rudolph, Christian Plank, Howard T. Jacobs, Marten Szibor
{"title":"Correction: Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active","authors":"Luca Giordano, Manish K. Aneja, Natascha Sommer, Nasim Alebrahimdehkordi, Alireza Seraji, Norbert Weissmann, Carsten Rudolph, Christian Plank, Howard T. Jacobs, Marten Szibor","doi":"10.1038/s41434-024-00473-x","DOIUrl":"10.1038/s41434-024-00473-x","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"528-528"},"PeriodicalIF":4.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00473-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1038/s41434-024-00476-8
Ivan Milenkovic, Shani Blumenreich, Ariel Hochfelder, Aviya Azulay, Inbal E. Biton, Mirie Zerbib, Roni Oren, Michael Tsoory, Tammar Joseph, Sarel J. Fleishman, Anthony H. Futerman
Almost all attempts to date at gene therapy approaches for monogenetic disease have used the amino acid sequences of the natural protein. In the current study, we use a designed, thermostable form of glucocerebrosidase (GCase), the enzyme defective in Gaucher disease (GD), to attempt to alleviate neurological symptoms in a GD mouse that models type 3 disease, i.e. the chronic neuronopathic juvenile subtype. Upon injection of an AAVrh10 (adeno-associated virus, serotype rh10) vector containing the designed GCase (dGCase) into the left lateral ventricle of Gba−/−;Gbatg mice, a significant improvement in body weight and life-span was observed, compared to injection of the same mouse with the wild type enzyme (wtGCase). Moreover, a reduction in levels of glucosylceramide (GlcCer), and an increase in levels of GCase activity were seen in the right hemisphere of Gba−/−;Gbatg mice, concomitantly with a significant improvement in motor function, reduction of neuroinflammation and a reduction in mRNA levels of various genes shown previously to be elevated in the brain of mouse models of neurological forms of GD. Together, these data pave the way for the possible use of modified proteins in gene therapy for lysosomal storage diseases and other monogenetic disorders.
{"title":"Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model","authors":"Ivan Milenkovic, Shani Blumenreich, Ariel Hochfelder, Aviya Azulay, Inbal E. Biton, Mirie Zerbib, Roni Oren, Michael Tsoory, Tammar Joseph, Sarel J. Fleishman, Anthony H. Futerman","doi":"10.1038/s41434-024-00476-8","DOIUrl":"10.1038/s41434-024-00476-8","url":null,"abstract":"Almost all attempts to date at gene therapy approaches for monogenetic disease have used the amino acid sequences of the natural protein. In the current study, we use a designed, thermostable form of glucocerebrosidase (GCase), the enzyme defective in Gaucher disease (GD), to attempt to alleviate neurological symptoms in a GD mouse that models type 3 disease, i.e. the chronic neuronopathic juvenile subtype. Upon injection of an AAVrh10 (adeno-associated virus, serotype rh10) vector containing the designed GCase (dGCase) into the left lateral ventricle of Gba−/−;Gbatg mice, a significant improvement in body weight and life-span was observed, compared to injection of the same mouse with the wild type enzyme (wtGCase). Moreover, a reduction in levels of glucosylceramide (GlcCer), and an increase in levels of GCase activity were seen in the right hemisphere of Gba−/−;Gbatg mice, concomitantly with a significant improvement in motor function, reduction of neuroinflammation and a reduction in mRNA levels of various genes shown previously to be elevated in the brain of mouse models of neurological forms of GD. Together, these data pave the way for the possible use of modified proteins in gene therapy for lysosomal storage diseases and other monogenetic disorders.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"439-444"},"PeriodicalIF":4.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00476-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1038/s41434-024-00477-7
Mengtian Cui, Qin Su, Mitchell Yip, Jackson McGowan, Claudio Punzo, Guangping Gao, Phillip W. L. Tai
Recombinant adeno-associated virus (rAAV) vectors are currently the only proven vehicles for treating ophthalmological diseases through gene therapy. A wide range of gene therapy programs that target ocular diseases are currently being pursued. Nearly 20 years of research have gone into enhancing the efficacy of targeting retinal tissues and improving transgene delivery to specific cell types. The engineered AAV capsid, AAV2.7m8 is currently among the best capsids for transducing the retina following intravitreal (IVT) injection. However, adverse effects, including intraocular inflammation, have been reported following retinal administration of AAV2.7m8 vectors in clinical trials. Furthermore, we have consistently observed that AAV2.7m8 exhibits low packaging titers irrespective of the vector construct design. In this report, we found that AAV2.7m8 packages vector genomes with a higher degree of heterogeneity than AAV2. We also found that genome-loaded AAV2.7m8 stimulated the infiltration of microglia in mouse retinas following IVT administration, while the response to genome-loaded AAV2 and empty AAV2.7m8 capsids produced much milder responses. This finding suggests that IVT administration of AAV2.7m8 vectors may stimulate retinal immune responses in part because of its penchant to package and deliver non-unit length genomes.
{"title":"The AAV2.7m8 capsid packages a higher degree of heterogeneous vector genomes than AAV2","authors":"Mengtian Cui, Qin Su, Mitchell Yip, Jackson McGowan, Claudio Punzo, Guangping Gao, Phillip W. L. Tai","doi":"10.1038/s41434-024-00477-7","DOIUrl":"10.1038/s41434-024-00477-7","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) vectors are currently the only proven vehicles for treating ophthalmological diseases through gene therapy. A wide range of gene therapy programs that target ocular diseases are currently being pursued. Nearly 20 years of research have gone into enhancing the efficacy of targeting retinal tissues and improving transgene delivery to specific cell types. The engineered AAV capsid, AAV2.7m8 is currently among the best capsids for transducing the retina following intravitreal (IVT) injection. However, adverse effects, including intraocular inflammation, have been reported following retinal administration of AAV2.7m8 vectors in clinical trials. Furthermore, we have consistently observed that AAV2.7m8 exhibits low packaging titers irrespective of the vector construct design. In this report, we found that AAV2.7m8 packages vector genomes with a higher degree of heterogeneity than AAV2. We also found that genome-loaded AAV2.7m8 stimulated the infiltration of microglia in mouse retinas following IVT administration, while the response to genome-loaded AAV2 and empty AAV2.7m8 capsids produced much milder responses. This finding suggests that IVT administration of AAV2.7m8 vectors may stimulate retinal immune responses in part because of its penchant to package and deliver non-unit length genomes.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"489-498"},"PeriodicalIF":4.6,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00477-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1038/s41434-024-00474-w
Rafael J. Yáñez-Muñoz, Jane E. Itzhaki
{"title":"Correction: Andrew C. G. Porter (1955–2023)","authors":"Rafael J. Yáñez-Muñoz, Jane E. Itzhaki","doi":"10.1038/s41434-024-00474-w","DOIUrl":"10.1038/s41434-024-00474-w","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"529-529"},"PeriodicalIF":4.6,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00474-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1038/s41434-024-00472-y
Sofia Bougioukli, Morgan Chateau, Heidy Morales, Venus Vakhshori, Osamu Sugiyama, Daniel Oakes, Donald Longjohn, Paula Cannon, Jay R. Lieberman
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