Pub Date : 2025-01-18DOI: 10.1038/s41434-025-00512-1
Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R. Marshall, Yanxia Yu, Zheng Wang
The approved intravenous adeno-associated virus (AAV) therapies are limited by the widespread prevalence of pre-existing anti-AAV antibodies in the general population, which are known to restrict patients’ ability to receive gene therapy and limit transfection efficacy in vivo. To address this challenge, we have developed a novel recombinant human immunoglobulin G degrading enzyme KJ103, characterized by low immunogenicity and clinical value for the elimination of anti-AAV antibodies in gene transfer. Herein, we conducted two randomized, blinded, placebo-controlled, single ascending dose Phase I studies in China and New Zealand, to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy volunteers. The results confirmed that KJ103 rapidly reduced IgG and maintained plasma IgG at low levels for one week. Dose of KJ103 ranging from 0.01 to 0.40 mg/kg had a favorable safety and tolerability profile across diverse ethnic and gender groups. KJ103 demonstrated a lower incidence of pre-existing anti-drug antibodies (ADAs) compared to currently approved human IgG degrading enzyme Imlifidase, with most induced ADAs predominantly reverting to baseline six months after administration. These properties are ideal for the management of immune disorders, rejection responses, and immunotherapies where pre-existing antibodies can reduce efficacy. Furthermore, we tested AAV2 neutralizing antibodies to confirm the potential utility of KJ103 in enhancing gene therapy.
{"title":"Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials","authors":"Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R. Marshall, Yanxia Yu, Zheng Wang","doi":"10.1038/s41434-025-00512-1","DOIUrl":"10.1038/s41434-025-00512-1","url":null,"abstract":"The approved intravenous adeno-associated virus (AAV) therapies are limited by the widespread prevalence of pre-existing anti-AAV antibodies in the general population, which are known to restrict patients’ ability to receive gene therapy and limit transfection efficacy in vivo. To address this challenge, we have developed a novel recombinant human immunoglobulin G degrading enzyme KJ103, characterized by low immunogenicity and clinical value for the elimination of anti-AAV antibodies in gene transfer. Herein, we conducted two randomized, blinded, placebo-controlled, single ascending dose Phase I studies in China and New Zealand, to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy volunteers. The results confirmed that KJ103 rapidly reduced IgG and maintained plasma IgG at low levels for one week. Dose of KJ103 ranging from 0.01 to 0.40 mg/kg had a favorable safety and tolerability profile across diverse ethnic and gender groups. KJ103 demonstrated a lower incidence of pre-existing anti-drug antibodies (ADAs) compared to currently approved human IgG degrading enzyme Imlifidase, with most induced ADAs predominantly reverting to baseline six months after administration. These properties are ideal for the management of immune disorders, rejection responses, and immunotherapies where pre-existing antibodies can reduce efficacy. Furthermore, we tested AAV2 neutralizing antibodies to confirm the potential utility of KJ103 in enhancing gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 3","pages":"223-236"},"PeriodicalIF":4.5,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004311","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 : 2025-01-10DOI: 10.1038/s41434-025-00513-0
Devesh C Pant, Sumit Verma
Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.
脊髓性肌萎缩症（SMA）是一种影响运动神经元的渐进性疾病，通常在婴儿期或儿童早期开始出现症状。最近，针对 SMA 的治疗取得了突破性进展，改善了婴幼儿患者的寿命和生活质量。鉴于这些治疗方法的影响，必须开发出管理治疗引起的疾病特征变化的方法。Zolgensma® 是第一种有效且已获批准的基因疗法，用于治疗由 SMN1 基因双偶联突变引起的 SMA。在接受 Zolgensma® 治疗的三名 SMA 患儿中，血浆中的神经元、神经胶质、炎症和血管标志物都表现出了较快的反应，强调了它们在临床试验中作为有价值的疗效生物标志物的潜力。我们选择了新颖的核酸关联免疫夹心测定法，以研究 SMA 患者在 Zolgensma® 治疗基线和 6 个月后采集的血浆样本中预先确定的神经炎症标记物。我们确定了一组新的靶标，其水平在 Zolgensma® 治疗前和治疗后组间存在差异，并且对治疗有反应。尽管我们的研究结果需要在更大的 SMA 群体和更长的随访时间中进行验证，但这些结果可能为在 SMA 临床试验中确定生物标志物终点的反应蛋白小组铺平了道路。
{"title":"Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy.","authors":"Devesh C Pant, Sumit Verma","doi":"10.1038/s41434-025-00513-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00513-0","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964493","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 : 2024-12-18DOI: 10.1038/s41434-024-00511-8
Lena C. Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C. Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J. Müller
Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding. This approach allowed us to distinguish capsids that only transduce cells based on genomic DNA (gDNA) from those also mediating transgene expression based on transcribed cDNA reads. After three rounds of selection on primary murine VSMCs (mVSMCs), we identified a novel targeting motif (RFTEKPA) that significantly improved transduction and gene expression efficiency over AAV9-wild type (WT) and increased expression in mVSMCs by 70% compared to the previously identified SLRSPPS peptide. Further analysis showed that the novel motif also improved expression in human aortic smooth muscle cells (HAoSMCs) and human aortic tissue ex vivo up to threefold compared to SLRSPPS and approximately 70-fold to AAV9-WT. This high cross-species transduction efficiency makes the novel capsid motif a potential candidate for future clinical application in vascular diseases.
{"title":"AAV library screening identifies novel vector for efficient transduction of human aorta","authors":"Lena C. Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C. Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J. Müller","doi":"10.1038/s41434-024-00511-8","DOIUrl":"10.1038/s41434-024-00511-8","url":null,"abstract":"Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding. This approach allowed us to distinguish capsids that only transduce cells based on genomic DNA (gDNA) from those also mediating transgene expression based on transcribed cDNA reads. After three rounds of selection on primary murine VSMCs (mVSMCs), we identified a novel targeting motif (RFTEKPA) that significantly improved transduction and gene expression efficiency over AAV9-wild type (WT) and increased expression in mVSMCs by 70% compared to the previously identified SLRSPPS peptide. Further analysis showed that the novel motif also improved expression in human aortic smooth muscle cells (HAoSMCs) and human aortic tissue ex vivo up to threefold compared to SLRSPPS and approximately 70-fold to AAV9-WT. This high cross-species transduction efficiency makes the novel capsid motif a potential candidate for future clinical application in vascular diseases.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"154-162"},"PeriodicalIF":4.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00511-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853989","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 : 2024-12-09DOI: 10.1038/s41434-024-00510-9
Jacqueline E. Hunter, Charles H. Vite, Caitlyn M. Molony, Patricia A. O’Donnell, John H. Wolfe
Widespread distribution of transduced brain cells following delivery of AAV vectors into the cerebrospinal fluid (CSF) of the cisterna magna (CM) has been demonstrated in large animal brains. In humans, intraventricular injection is preferred to intracisternal injection for CSF delivery due to the risk of brain stem injury. One study in the dog reported adverse reactions to AAV vectors expressing GFP injected into the lateral ventricle but not when injected into the CM. In contrast, AAV expressing mammalian genes in diseased animals have not triggered adverse responses since many genetic diseases also have compromised immune systems. Differences in circulation of CSF from each site could potentially affect vector spread within the brain, but a direct comparison has not been made using both a mammalian gene and immunologically normal animals. In this study we evaluated the dopamine-2-receptor (D2R) variant D2R80A, which is inactivated for intracellular signaling and has been used as a reporter gene in large animal brains. No adverse reactions to the D2R80A gene were observed from either injection route in normal dogs and both routes resulted in comparable distribution of D2R80A within the brain.
{"title":"Intracisternal vs intraventricular injection of AAV1 result in comparable, widespread transduction of the dog brain","authors":"Jacqueline E. Hunter, Charles H. Vite, Caitlyn M. Molony, Patricia A. O’Donnell, John H. Wolfe","doi":"10.1038/s41434-024-00510-9","DOIUrl":"10.1038/s41434-024-00510-9","url":null,"abstract":"Widespread distribution of transduced brain cells following delivery of AAV vectors into the cerebrospinal fluid (CSF) of the cisterna magna (CM) has been demonstrated in large animal brains. In humans, intraventricular injection is preferred to intracisternal injection for CSF delivery due to the risk of brain stem injury. One study in the dog reported adverse reactions to AAV vectors expressing GFP injected into the lateral ventricle but not when injected into the CM. In contrast, AAV expressing mammalian genes in diseased animals have not triggered adverse responses since many genetic diseases also have compromised immune systems. Differences in circulation of CSF from each site could potentially affect vector spread within the brain, but a direct comparison has not been made using both a mammalian gene and immunologically normal animals. In this study we evaluated the dopamine-2-receptor (D2R) variant D2R80A, which is inactivated for intracellular signaling and has been used as a reporter gene in large animal brains. No adverse reactions to the D2R80A gene were observed from either injection route in normal dogs and both routes resulted in comparable distribution of D2R80A within the brain.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 3","pages":"184-188"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800312","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 : 2024-12-04DOI: 10.1038/s41434-024-00508-3
Baylea N. Davenport, Rebecca L. Wilson, Alyssa A. Williams, Helen N. Jones
Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.
{"title":"Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model","authors":"Baylea N. Davenport, Rebecca L. Wilson, Alyssa A. Williams, Helen N. Jones","doi":"10.1038/s41434-024-00508-3","DOIUrl":"10.1038/s41434-024-00508-3","url":null,"abstract":"Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 3","pages":"255-265"},"PeriodicalIF":4.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767986","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 : 2024-11-29DOI: 10.1038/s41434-024-00507-4
Yu Zhou, Tina Sach, Joseph Y. Ong, Ting-An Lim, Zoltan Berecz, Colin Deniston, Goran Milicic, Connie Y. Tsai, Taryn Kandepalli, Derek J. Langeslay, Qiang Qin
Recombinant adeno-associated viral (AAV) vectors have emerged as prominent gene delivery vehicles for gene therapy. In the journey of an AAV vector, AAV vectors can be exposed to different proteolytic environments inside the production cells, during the cell lysis step, within the endosome, and finally inside the cell nucleus. The stability of a modified AAV serotype 2 (AAV2) capsid was evaluated via a proteolytic approach using trypsin and other proteases and both denaturing and non-denaturing analytical methods. Trypsin digestion of the AAV2 capsids resulted in clips of the capsid proteins at the C-terminus as confirmed by denaturing methods including SDS-PAGE, CE-SDS, Western blot, and RPLC-MS. It was found that the AAV2 capsid with clips not only remains structurally intact, as confirmed by non-denaturing methods including SEC, thermostability testing, and cryo-EM, but also remains potent, as confirmed in a cell-based potency assay. This finding reveals that AAV2 capsid with proteolytic cuts remains intact and potent since the icosahedral three-dimensional structural arrangement of AAV capsid proteins can protect the clipped fragment from being released from the capsid, such that the AAV capsid remains intact allowing for the functionality to be maintained to deliver the DNA in the host cell. Evaluation of AAV stability using a proteolytic approach and multiple denaturing and non-denaturing analytical methods can provide valuable information for engineering AAV capsids to develop AAV-based gene therapy.
{"title":"Adeno-associated virus serotype 2 capsids with proteolytic cuts by trypsin remain intact and potent","authors":"Yu Zhou, Tina Sach, Joseph Y. Ong, Ting-An Lim, Zoltan Berecz, Colin Deniston, Goran Milicic, Connie Y. Tsai, Taryn Kandepalli, Derek J. Langeslay, Qiang Qin","doi":"10.1038/s41434-024-00507-4","DOIUrl":"10.1038/s41434-024-00507-4","url":null,"abstract":"Recombinant adeno-associated viral (AAV) vectors have emerged as prominent gene delivery vehicles for gene therapy. In the journey of an AAV vector, AAV vectors can be exposed to different proteolytic environments inside the production cells, during the cell lysis step, within the endosome, and finally inside the cell nucleus. The stability of a modified AAV serotype 2 (AAV2) capsid was evaluated via a proteolytic approach using trypsin and other proteases and both denaturing and non-denaturing analytical methods. Trypsin digestion of the AAV2 capsids resulted in clips of the capsid proteins at the C-terminus as confirmed by denaturing methods including SDS-PAGE, CE-SDS, Western blot, and RPLC-MS. It was found that the AAV2 capsid with clips not only remains structurally intact, as confirmed by non-denaturing methods including SEC, thermostability testing, and cryo-EM, but also remains potent, as confirmed in a cell-based potency assay. This finding reveals that AAV2 capsid with proteolytic cuts remains intact and potent since the icosahedral three-dimensional structural arrangement of AAV capsid proteins can protect the clipped fragment from being released from the capsid, such that the AAV capsid remains intact allowing for the functionality to be maintained to deliver the DNA in the host cell. Evaluation of AAV stability using a proteolytic approach and multiple denaturing and non-denaturing analytical methods can provide valuable information for engineering AAV capsids to develop AAV-based gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"121-131"},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00507-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754970","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 : 2024-11-28DOI: 10.1038/s41434-024-00499-1
Joss B. Murray, Patrick T. Harrison, Janine Scholefield
We are often confronted with a simple question, “which gene editing technique is the best?”; the simple answer is “there isn’t one”. In 2021, a year after prime editing first made its mark, we evaluated the landscape of this potentially transformative advance in genome engineering towards getting treatments to the clinic [1]. Nearly 20% of the papers we cited were still in pre-print at the time which serves to indicate how early-stage the knowledge base was at that time. Now, three years later, we take a look at the landscape and ask what has been learnt to ensure this tech is broadly accessible, highlighting some key advances, especially those that push this towards the clinic. A big part of the appeal of prime editing is its ability to precisely edit DNA without double stranded breaks, and to install any of the 12 possible single-nucleotide conversion events as well as small insertions and/or deletions, or essentially any combination thereof. Over the last few decades, other transformative and Nobel prize-winning technologies that rely on Watson-Crick base-pairing such as PCR, site-directed mutagenesis, RNA interference, and one might say, “classic” CRISPR, were swiftly adopted across labs around the world because of the speed with which mechanistic rules governing their efficiency were determined. Whilst this perspective focuses on the context of gene therapy applications of prime editing, we also further look at the recent studies which have increased our understanding of the mechanism of PEs and simultaneously improved the efficiency and diversity of the PE toolbox.
{"title":"Prime editing: therapeutic advances and mechanistic insights","authors":"Joss B. Murray, Patrick T. Harrison, Janine Scholefield","doi":"10.1038/s41434-024-00499-1","DOIUrl":"10.1038/s41434-024-00499-1","url":null,"abstract":"We are often confronted with a simple question, “which gene editing technique is the best?”; the simple answer is “there isn’t one”. In 2021, a year after prime editing first made its mark, we evaluated the landscape of this potentially transformative advance in genome engineering towards getting treatments to the clinic [1]. Nearly 20% of the papers we cited were still in pre-print at the time which serves to indicate how early-stage the knowledge base was at that time. Now, three years later, we take a look at the landscape and ask what has been learnt to ensure this tech is broadly accessible, highlighting some key advances, especially those that push this towards the clinic. A big part of the appeal of prime editing is its ability to precisely edit DNA without double stranded breaks, and to install any of the 12 possible single-nucleotide conversion events as well as small insertions and/or deletions, or essentially any combination thereof. Over the last few decades, other transformative and Nobel prize-winning technologies that rely on Watson-Crick base-pairing such as PCR, site-directed mutagenesis, RNA interference, and one might say, “classic” CRISPR, were swiftly adopted across labs around the world because of the speed with which mechanistic rules governing their efficiency were determined. Whilst this perspective focuses on the context of gene therapy applications of prime editing, we also further look at the recent studies which have increased our understanding of the mechanism of PEs and simultaneously improved the efficiency and diversity of the PE toolbox.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"83-92"},"PeriodicalIF":4.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00499-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750784","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}
Despite numerous studies identifying the advantages of therapies for spinal muscular atrophy (SMA), healthcare professionals encounter obstacles in determining the most effective treatment. This study aimed to investigate the effects of gene-based therapy for SMA. A systematic search was conducted from inception to May 2024 across databases, and all studies assessing the effects of gene-based therapy on patients with SMA types 1 and 2 were included. The outcomes measured were survival, the need for ventilatory support, improvements in motor function, and the occurrence of adverse drug reactions. Meta-analyses were performed using a random-effects model. A total of 57 studies (n = 3418) were included, and the meta-analyses revealed that onasemnogene abeparvovec showed the highest survival rate (95% [95% CI: 88, 100]), followed by risdiplam (86% [95% CI: 76, 94]) and nusinersen (60% [95% CI: 50, 70]). The number of patients needing ventilatory support was reduced after treatment with onasemnogene abeparvovec (risk ratio = 0·10 [95% CI: 0·02, 0·53]). Onasemnogene abeparvovec and risdiplam had similar proportions of patients with improvements in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders score of ≥4 points (92% [95% CI: 62, 100] vs 90% [95% CI: 77, 97]). In contrast, nusinersen had the smallest improvement (74% [95% CI: 66, 81]). The most frequently observed adverse drug reactions were headaches, vomiting, and gastrointestinal disorders. Gene-based therapy benefits patient survival and improves motor function. Onasemnogene abeparvovec and risdiplam appear highly effective, whereas nusinersen exhibits moderate effectiveness.
{"title":"Gene-based therapy for the treatment of spinal muscular atrophy types 1 and 2 : a systematic review and meta-analysis","authors":"Bunchai Chongmelaxme, Varalee Yodsurang, Ponlawat Vichayachaipat, Thanate Srimatimanon, Oranee Sanmaneechai","doi":"10.1038/s41434-024-00503-8","DOIUrl":"10.1038/s41434-024-00503-8","url":null,"abstract":"Despite numerous studies identifying the advantages of therapies for spinal muscular atrophy (SMA), healthcare professionals encounter obstacles in determining the most effective treatment. This study aimed to investigate the effects of gene-based therapy for SMA. A systematic search was conducted from inception to May 2024 across databases, and all studies assessing the effects of gene-based therapy on patients with SMA types 1 and 2 were included. The outcomes measured were survival, the need for ventilatory support, improvements in motor function, and the occurrence of adverse drug reactions. Meta-analyses were performed using a random-effects model. A total of 57 studies (n = 3418) were included, and the meta-analyses revealed that onasemnogene abeparvovec showed the highest survival rate (95% [95% CI: 88, 100]), followed by risdiplam (86% [95% CI: 76, 94]) and nusinersen (60% [95% CI: 50, 70]). The number of patients needing ventilatory support was reduced after treatment with onasemnogene abeparvovec (risk ratio = 0·10 [95% CI: 0·02, 0·53]). Onasemnogene abeparvovec and risdiplam had similar proportions of patients with improvements in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders score of ≥4 points (92% [95% CI: 62, 100] vs 90% [95% CI: 77, 97]). In contrast, nusinersen had the smallest improvement (74% [95% CI: 66, 81]). The most frequently observed adverse drug reactions were headaches, vomiting, and gastrointestinal disorders. Gene-based therapy benefits patient survival and improves motor function. Onasemnogene abeparvovec and risdiplam appear highly effective, whereas nusinersen exhibits moderate effectiveness.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 4","pages":"301-330"},"PeriodicalIF":4.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739263","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}
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