{"title":"Duchenne muscular dystrophy: diagnosis and perspective of treatment","authors":"Corrado Angelini","doi":"10.20517/jtgg.2024.29","DOIUrl":"https://doi.org/10.20517/jtgg.2024.29","url":null,"abstract":"","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"12 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Gross, Sana Z. Mahmood, E. Dombi, Markku M. Miettinen, Mark Raffeld, Anne Dufek, Sneh Patel, Prashant Chittiboina, Brigitte C. Widemann
Atypical neurofibromas (aNF) are peripheral nerve sheath tumors (PNSTs) histologically defined by cytologic atypia, hypercellularity, loss of neurofibroma architecture, and/or increased mitotic activity. aNF often have a heterozygous loss of CDKN2A/B in addition to homozygous NF1 loss. On MRI, aNF frequently appear as distinct nodular lesions, grow faster than plexiform neurofibromas, and have increased avidity on fluorodeoxyglucose positron emission tomography. At least some aNF are considered to be at greater risk for transformation to highly aggressive malignant PNSTs. We have observed that some PNSTs demonstrate a discrepancy between histological, clinical, and genomic criteria, where a PNST without histologically concerning findings may have clinical and imaging features concerning aNF and CDKN2A/B loss. This case series highlights this discrepancy and suggests the inclusion of CDKN2A/B loss to define aNF, along with clinical and imaging findings, to determine the potential for malignant transformation, and to select appropriate clinical management.
{"title":"Challenges in determining the malignant potential of atypical neurofibromas (aNF) using histopathologic features and the potential need for CDKN2A/2B testing: a case report","authors":"A. Gross, Sana Z. Mahmood, E. Dombi, Markku M. Miettinen, Mark Raffeld, Anne Dufek, Sneh Patel, Prashant Chittiboina, Brigitte C. Widemann","doi":"10.20517/jtgg.2024.02","DOIUrl":"https://doi.org/10.20517/jtgg.2024.02","url":null,"abstract":"Atypical neurofibromas (aNF) are peripheral nerve sheath tumors (PNSTs) histologically defined by cytologic atypia, hypercellularity, loss of neurofibroma architecture, and/or increased mitotic activity. aNF often have a heterozygous loss of CDKN2A/B in addition to homozygous NF1 loss. On MRI, aNF frequently appear as distinct nodular lesions, grow faster than plexiform neurofibromas, and have increased avidity on fluorodeoxyglucose positron emission tomography. At least some aNF are considered to be at greater risk for transformation to highly aggressive malignant PNSTs. We have observed that some PNSTs demonstrate a discrepancy between histological, clinical, and genomic criteria, where a PNST without histologically concerning findings may have clinical and imaging features concerning aNF and CDKN2A/B loss. This case series highlights this discrepancy and suggests the inclusion of CDKN2A/B loss to define aNF, along with clinical and imaging findings, to determine the potential for malignant transformation, and to select appropriate clinical management.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"7 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140673498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Bliden, Sahib Singh, Roni Shanoada, Isha Kalia, U. Tantry, Alyssa Zimmerman, A. D. Babu, Lekshminarayan Raghavakurup, Taylor Stude, Damian Sidorski, Paul A Gurbel
Cardiovascular diseases (CVDs) remain one of the leading causes of morbidity and mortality worldwide, with genetics being a major risk factor. Genetic cardiovascular disease can occur either because of single variant (Mendelian) or polygenic influences and has been linked to inherited cardiovascular conditions (ICC) such as arrhythmias, cardiomyopathies, dyslipidemias, and aortopathies which are significant factors leading to sudden cardiac death in young adults. Timely screening, diagnosis, and management of ICC can not only provide life-saving treatment to a patient, but also identify at-risk family members. The field of pharmacogenomics (PGx) helped to understand the variable action of medications such as clopidogrel, aspirin, warfarin, and statin according to genotype. Newer technologies such as multi-omics can combine data from multiple sources such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome. These advancements can contribute to the development of polygenic prediction scores and precision medicine tailored to individual genotypes. Substantial strides have been made in genetic-based therapeutics, gene editing technologies, and drug delivery systems, which have significantly expanded treatment options for patients with acquired or inherited CVDs. Although variable, the country- and society-specific guidelines on genetic testing for ICC and PGx and treatment are being continuously updated to keep up with ongoing research in the field. Along with appropriate knowledge, other factors including cost and availability of genetic testing play a vital role in the usage by both physicians and patients. With the advent of newer genetic testing for CVDs, a key factor is the availability of genetic counselors (GCs) who are specifically trained in cardiovascular genomics. The current review provides a concise summary of the major influences of genetics in the diagnosis and treatment of CVDs.
{"title":"Genetics in the diagnosis and treatment of cardiovascular diseases","authors":"K. Bliden, Sahib Singh, Roni Shanoada, Isha Kalia, U. Tantry, Alyssa Zimmerman, A. D. Babu, Lekshminarayan Raghavakurup, Taylor Stude, Damian Sidorski, Paul A Gurbel","doi":"10.20517/jtgg.2023.59","DOIUrl":"https://doi.org/10.20517/jtgg.2023.59","url":null,"abstract":"Cardiovascular diseases (CVDs) remain one of the leading causes of morbidity and mortality worldwide, with genetics being a major risk factor. Genetic cardiovascular disease can occur either because of single variant (Mendelian) or polygenic influences and has been linked to inherited cardiovascular conditions (ICC) such as arrhythmias, cardiomyopathies, dyslipidemias, and aortopathies which are significant factors leading to sudden cardiac death in young adults. Timely screening, diagnosis, and management of ICC can not only provide life-saving treatment to a patient, but also identify at-risk family members. The field of pharmacogenomics (PGx) helped to understand the variable action of medications such as clopidogrel, aspirin, warfarin, and statin according to genotype. Newer technologies such as multi-omics can combine data from multiple sources such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome. These advancements can contribute to the development of polygenic prediction scores and precision medicine tailored to individual genotypes. Substantial strides have been made in genetic-based therapeutics, gene editing technologies, and drug delivery systems, which have significantly expanded treatment options for patients with acquired or inherited CVDs. Although variable, the country- and society-specific guidelines on genetic testing for ICC and PGx and treatment are being continuously updated to keep up with ongoing research in the field. Along with appropriate knowledge, other factors including cost and availability of genetic testing play a vital role in the usage by both physicians and patients. With the advent of newer genetic testing for CVDs, a key factor is the availability of genetic counselors (GCs) who are specifically trained in cardiovascular genomics. The current review provides a concise summary of the major influences of genetics in the diagnosis and treatment of CVDs.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"53 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140700357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ahmed Kamal, M. Swellam, N. Shalaby, Marwa K. Darwish, E. El-Nahrery
Long non-coding RNAs (lncRNAs) are a class of RNA transcripts that are long (i.e., more than 200 nucleotides) and not translated into proteins. They have recently emerged as potential treatment targets for numerous disorders due to their involvement in multiple cellular functions such as gene regulation, epigenetic modulation, and chromatin organization. This review highlights the current state of lncRNA-based therapeutics, the potential of lncRNAs as drug targets for treating human diseases, the various strategies and types of RNA-based therapeutics, and the complications of developing lncRNA-based drugs. We conclude that lncRNA-based therapeutics represent a promising class of drugs that can potentially treat various human diseases and that further research is needed to fully realize their therapeutic potential.
{"title":"Silent players, loud impact: unveiling the therapeutic potentials of LncRNAs","authors":"Ahmed Kamal, M. Swellam, N. Shalaby, Marwa K. Darwish, E. El-Nahrery","doi":"10.20517/jtgg.2023.55","DOIUrl":"https://doi.org/10.20517/jtgg.2023.55","url":null,"abstract":"Long non-coding RNAs (lncRNAs) are a class of RNA transcripts that are long (i.e., more than 200 nucleotides) and not translated into proteins. They have recently emerged as potential treatment targets for numerous disorders due to their involvement in multiple cellular functions such as gene regulation, epigenetic modulation, and chromatin organization. This review highlights the current state of lncRNA-based therapeutics, the potential of lncRNAs as drug targets for treating human diseases, the various strategies and types of RNA-based therapeutics, and the complications of developing lncRNA-based drugs. We conclude that lncRNA-based therapeutics represent a promising class of drugs that can potentially treat various human diseases and that further research is needed to fully realize their therapeutic potential.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"56 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140733660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-05-29DOI: 10.20517/jtgg.2024.11
Edgard M Mejia, Genevieve C Sparagna, Donald W Miller, Grant M Hatch
Aim: Barth syndrome (BTHS) is a rare X-linked genetic disease in which mitochondrial oxidative phosphorylation is impaired due to a mutation in the TAFAZZIN gene. The protein kinase C delta (PKCδ) signalosome exists as a high molecular weight complex in mitochondria and controls mitochondrial oxidative phosphorylation.
Method: Here, we examined PKCδ levels in mitochondria of aged-matched control and BTHS patient B lymphoblasts and its association with a higher molecular weight complex in mitochondria.
Result: Immunoblot analysis of blue-native polyacrylamide gel electrophoresis mitochondrial fractions revealed an increase in total PKCδ protein expression in BTHS lymphoblasts compared to controls. In contrast, PKCδ associated with a higher molecular weight complex was markedly reduced in BTHS patient B lymphoblasts compared to controls. Given the decrease in PKCδ associated with a higher molecular weight complex in mitochondria, we examined the uptake of creatine, a compound whose utilization is enhanced upon high energy demand. Creatine uptake was markedly elevated in BTHS lymphoblasts compared to controls.
Conclusion: We hypothesize that reduced PKCδ within this higher molecular weight complex in mitochondria may contribute to the bioenergetic defects observed in BTHS lymphoblasts and that enhanced creatine uptake may serve as one of several compensatory mechanisms for the defective mitochondrial oxidative phosphorylation observed in these cells.
目的：巴特综合征（BTHS）是一种罕见的X连锁遗传病，由于TAFAZZIN基因突变导致线粒体氧化磷酸化功能受损。蛋白激酶 C δ（PKCδ）信号体在线粒体中以高分子量复合物的形式存在，控制线粒体氧化磷酸化：在此，我们研究了与年龄匹配的对照组和BTHS患者B淋巴细胞线粒体中的PKCδ水平及其与线粒体中高分子量复合物的关联：结果：对蓝色原性聚丙烯酰胺凝胶电泳线粒体部分进行的免疫印迹分析表明，与对照组相比，BTHS淋巴细胞中总PKCδ蛋白表达量有所增加。相反，与对照组相比，BTHS 患者 B 淋巴细胞中与较高分子量复合物相关的 PKCδ 蛋白明显减少。鉴于线粒体中与较高分子量复合物相关的 PKCδ 减少，我们对肌酸的摄取进行了研究，肌酸是一种在高能量需求时利用率较高的化合物。与对照组相比，BTHS淋巴母细胞对肌酸的摄取明显增加：我们推测，线粒体中这一较高分子量复合物中的 PKCδ 减少可能是导致 BTHS 淋巴母细胞生物能缺陷的原因之一，而肌酸摄取的增强可能是这些细胞中线粒体氧化磷酸化缺陷的几种补偿机制之一。
{"title":"Reduced protein kinase C delta in a high molecular weight complex in mitochondria and elevated creatine uptake into Barth syndrome B lymphoblasts.","authors":"Edgard M Mejia, Genevieve C Sparagna, Donald W Miller, Grant M Hatch","doi":"10.20517/jtgg.2024.11","DOIUrl":"10.20517/jtgg.2024.11","url":null,"abstract":"<p><strong>Aim: </strong>Barth syndrome (BTHS) is a rare X-linked genetic disease in which mitochondrial oxidative phosphorylation is impaired due to a mutation in the <i>TAFAZZIN</i> gene. The protein kinase C delta (PKCδ) signalosome exists as a high molecular weight complex in mitochondria and controls mitochondrial oxidative phosphorylation.</p><p><strong>Method: </strong>Here, we examined PKCδ levels in mitochondria of aged-matched control and BTHS patient B lymphoblasts and its association with a higher molecular weight complex in mitochondria.</p><p><strong>Result: </strong>Immunoblot analysis of blue-native polyacrylamide gel electrophoresis mitochondrial fractions revealed an increase in total PKCδ protein expression in BTHS lymphoblasts compared to controls. In contrast, PKCδ associated with a higher molecular weight complex was markedly reduced in BTHS patient B lymphoblasts compared to controls. Given the decrease in PKCδ associated with a higher molecular weight complex in mitochondria, we examined the uptake of creatine, a compound whose utilization is enhanced upon high energy demand. Creatine uptake was markedly elevated in BTHS lymphoblasts compared to controls.</p><p><strong>Conclusion: </strong>We hypothesize that reduced PKCδ within this higher molecular weight complex in mitochondria may contribute to the bioenergetic defects observed in BTHS lymphoblasts and that enhanced creatine uptake may serve as one of several compensatory mechanisms for the defective mitochondrial oxidative phosphorylation observed in these cells.</p>","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"8 ","pages":"216-224"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autism spectrum disorder (ASD) is a behaviorally defined syndrome affected by multiple genetic and environmental factors. A wide variety of risk factors for ASD have been identified and many of these affect immune functions. This may not be surprising, since the immune system and the nervous system share common signaling mechanisms and affect each other as a part of the neuroimmune network. The ever-expanding scope of inborn errors of immunity (IEIs) has revealed multiple pathogenic gene variants that manifest overlapping clinical features of common neuropsychiatric diseases, including ASD. These IEIs often cause dysregulated immune activation and resultant chronic inflammation affecting multiple organs. Some IEIs also cause changes in morphogenesis and plasticity of the central nervous system. Such patients often present with a puzzling array of clinical features and some of them may be diagnosed with ASD or other neuropsychiatric conditions. The progress of our understanding of disease mechanisms for IEIs at the molecular levels has led to gene-specific treatment measures in some diseases. In addition, some ASD patients are found to have laboratory findings of neuroinflammation that resemble those seen in IEI patients. This may pave the way for applying specific treatment measures used for IEI patients in such ASD patients. This review focuses on describing IEIs that have overlapping features of ASD. Emphasis is also on IEIs that can be treated by targeting identified disease mechanisms. Such information may be helpful for clinicians who are considering genetic/metabolic workup in ASD patients.
{"title":"Inborn errors of immunity present with neuropsychiatric symptoms overlapping with autistic behavioral symptoms","authors":"Harumi Jyonouchi","doi":"10.20517/jtgg.2023.32","DOIUrl":"https://doi.org/10.20517/jtgg.2023.32","url":null,"abstract":"Autism spectrum disorder (ASD) is a behaviorally defined syndrome affected by multiple genetic and environmental factors. A wide variety of risk factors for ASD have been identified and many of these affect immune functions. This may not be surprising, since the immune system and the nervous system share common signaling mechanisms and affect each other as a part of the neuroimmune network. The ever-expanding scope of inborn errors of immunity (IEIs) has revealed multiple pathogenic gene variants that manifest overlapping clinical features of common neuropsychiatric diseases, including ASD. These IEIs often cause dysregulated immune activation and resultant chronic inflammation affecting multiple organs. Some IEIs also cause changes in morphogenesis and plasticity of the central nervous system. Such patients often present with a puzzling array of clinical features and some of them may be diagnosed with ASD or other neuropsychiatric conditions. The progress of our understanding of disease mechanisms for IEIs at the molecular levels has led to gene-specific treatment measures in some diseases. In addition, some ASD patients are found to have laboratory findings of neuroinflammation that resemble those seen in IEI patients. This may pave the way for applying specific treatment measures used for IEI patients in such ASD patients. This review focuses on describing IEIs that have overlapping features of ASD. Emphasis is also on IEIs that can be treated by targeting identified disease mechanisms. Such information may be helpful for clinicians who are considering genetic/metabolic workup in ASD patients.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"115 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138994119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Moebius Syndrome (MBS) is a rare neurodevelopmental disorder characterised by facial paralysis and ocular motility defects. Its origins trace back to the 19th century, with its clinical delineation attributed to German neurologist Paul Möbius. The syndrome presents with a spectrum of variable systemic clinical features, necessitating a multidisciplinary approach to diagnosis and management. The prevalence of MBS has been estimated to range between 1 in 50,000 to 1 in 500,000 individuals, with a universal distribution across ethnicities and genders. The aetiology of MBS is poorly understood but is likely multifactorial, with developmental, genetic, and environmental factors playing roles. Recent research has identified potential genetic contributors, REV3L and PLXND1, but further work is needed to elucidate the genetic landscape of this rare neurodevelopmental disorder. Here we describe the current understanding of the clinical features, aetiology, genetic landscape, and management of MBS, emphasising the importance of early diagnosis and a holistic approach to patient care. We also propose a set of criteria aimed at standardising MBS reporting to enhance information sharing and bolster MBS research initiatives. Collaborative research efforts in the future hold the potential to offer transformative insights and improved outcomes for affected individuals and their families.
{"title":"Towards an understanding of the aetiology, genomic landscape and management of Moebius syndrome","authors":"Ekaterina Lyulcheva-Bennett, Wendy Blumenow, Adelene O’Connor, Maria Kelly, Daimark Bennett, Adel Fattah","doi":"10.20517/jtgg.2023.33","DOIUrl":"https://doi.org/10.20517/jtgg.2023.33","url":null,"abstract":"Moebius Syndrome (MBS) is a rare neurodevelopmental disorder characterised by facial paralysis and ocular motility defects. Its origins trace back to the 19th century, with its clinical delineation attributed to German neurologist Paul Möbius. The syndrome presents with a spectrum of variable systemic clinical features, necessitating a multidisciplinary approach to diagnosis and management. The prevalence of MBS has been estimated to range between 1 in 50,000 to 1 in 500,000 individuals, with a universal distribution across ethnicities and genders. The aetiology of MBS is poorly understood but is likely multifactorial, with developmental, genetic, and environmental factors playing roles. Recent research has identified potential genetic contributors, REV3L and PLXND1, but further work is needed to elucidate the genetic landscape of this rare neurodevelopmental disorder. Here we describe the current understanding of the clinical features, aetiology, genetic landscape, and management of MBS, emphasising the importance of early diagnosis and a holistic approach to patient care. We also propose a set of criteria aimed at standardising MBS reporting to enhance information sharing and bolster MBS research initiatives. Collaborative research efforts in the future hold the potential to offer transformative insights and improved outcomes for affected individuals and their families.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"7 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138971598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mutations in mitochondrial DNA can cause mitochondrial diseases. This review focuses on the main functions of mitochondria and the effect of mutations in mtDNA on the processes of mitophagy, mitodynamics and mitochondrial biogenesis. The main mitochondrial diseases associated with specific mutations in mtDNA are reviewed, with an emphasis on atherosclerosis. It is assumed that mtDNA mutations can provoke pathological changes in the intima of the human aorta and activate a specific immune response, ultimately leading to the development of atherosclerosis. Special attention is paid to the methods of targeted therapy of mitochondrial diseases with the use of antioxidants, mitodynamics modifiers, and phototheranostics.
{"title":"Drug-based approaches to modulate mitochondrial condition in the case of atherosclerosis: focus on correction of mitochondria dysfunction","authors":"Darina Gavrilova, Evgeny Bezsonov, Tatyana Degtyarevskaya","doi":"10.20517/jtgg.2023.38","DOIUrl":"https://doi.org/10.20517/jtgg.2023.38","url":null,"abstract":"Mutations in mitochondrial DNA can cause mitochondrial diseases. This review focuses on the main functions of mitochondria and the effect of mutations in mtDNA on the processes of mitophagy, mitodynamics and mitochondrial biogenesis. The main mitochondrial diseases associated with specific mutations in mtDNA are reviewed, with an emphasis on atherosclerosis. It is assumed that mtDNA mutations can provoke pathological changes in the intima of the human aorta and activate a specific immune response, ultimately leading to the development of atherosclerosis. Special attention is paid to the methods of targeted therapy of mitochondrial diseases with the use of antioxidants, mitodynamics modifiers, and phototheranostics.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"32 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138592258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lara V. Graham, J. G. Fisher, S. Khakoo, Matthew D. Blunt
Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.
{"title":"Targeting KIR as a novel approach to improve CAR-NK cell function","authors":"Lara V. Graham, J. G. Fisher, S. Khakoo, Matthew D. Blunt","doi":"10.20517/jtgg.2023.25","DOIUrl":"https://doi.org/10.20517/jtgg.2023.25","url":null,"abstract":"Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"132 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138598986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leire Bergara-Muguruza, A. Castellanos-Rubio, I. Santin, A. Olazagoitia-Garmendia
Development of new high throughput array-based techniques and, more recently, next-generation sequencing (NGS) technologies have revolutionized our capability to accurately characterize single nucleotide polymorphisms (SNPs) throughout the genome. These advances have facilitated large-scale genome-wide association studies (GWAS), which have served as fundamental elements in establishing links between SNPs and the susceptibility to several complex diseases, including those related to the immune system. Nevertheless, the molecular mechanisms underlying the development of most of these disorders are still poorly defined. Decoding the functionality of SNPs becomes increasingly challenging due to the predominant presence of these risk variants in non-coding regions of the genome. Among them, long non-coding RNAs (lncRNAs) are enriched in disease-associated SNPs. lncRNAs are involved in governing the control of gene expression both during transcription and at the post-transcriptional level. The existence of SNPs within the sequences of lncRNAs has the potential to alter their expression, structure, or function. This, in turn, can influence their regulatory roles and consequently contribute to the onset or progression of various diseases. In this review, we describe the implication of SNPs located in lncRNAs in the development of different immune-related diseases and highlight the potential of these molecules in the development of emerging RNA-based therapies.
新的高通量阵列技术以及最近的新一代测序（NGS）技术的发展，彻底改变了我们准确描述整个基因组中单核苷酸多态性（SNPs）的能力。这些进步促进了大规模的全基因组关联研究（GWAS），这些研究是建立 SNP 与多种复杂疾病（包括与免疫系统相关的疾病）易感性之间联系的基本要素。尽管如此，这些疾病中大多数的发病分子机制仍不十分明确。由于这些风险变异主要存在于基因组的非编码区，解码 SNP 的功能变得越来越具有挑战性。其中，长非编码 RNA（lncRNA）富含与疾病相关的 SNPs。lncRNA 在转录过程中和转录后水平上参与控制基因表达。lncRNA 序列中存在的 SNPs 有可能改变其表达、结构或功能。这反过来又会影响它们的调控作用，从而导致各种疾病的发生或发展。在这篇综述中，我们描述了位于 lncRNA 中的 SNPs 在不同免疫相关疾病的发展中的影响，并强调了这些分子在开发基于 RNA 的新兴疗法中的潜力。
{"title":"lncRNA involvement in immune-related diseases - from SNP association to implication in pathogenesis and therapeutic potential","authors":"Leire Bergara-Muguruza, A. Castellanos-Rubio, I. Santin, A. Olazagoitia-Garmendia","doi":"10.20517/jtgg.2023.14","DOIUrl":"https://doi.org/10.20517/jtgg.2023.14","url":null,"abstract":"Development of new high throughput array-based techniques and, more recently, next-generation sequencing (NGS) technologies have revolutionized our capability to accurately characterize single nucleotide polymorphisms (SNPs) throughout the genome. These advances have facilitated large-scale genome-wide association studies (GWAS), which have served as fundamental elements in establishing links between SNPs and the susceptibility to several complex diseases, including those related to the immune system. Nevertheless, the molecular mechanisms underlying the development of most of these disorders are still poorly defined. Decoding the functionality of SNPs becomes increasingly challenging due to the predominant presence of these risk variants in non-coding regions of the genome. Among them, long non-coding RNAs (lncRNAs) are enriched in disease-associated SNPs. lncRNAs are involved in governing the control of gene expression both during transcription and at the post-transcriptional level. The existence of SNPs within the sequences of lncRNAs has the potential to alter their expression, structure, or function. This, in turn, can influence their regulatory roles and consequently contribute to the onset or progression of various diseases. In this review, we describe the implication of SNPs located in lncRNAs in the development of different immune-related diseases and highlight the potential of these molecules in the development of emerging RNA-based therapies.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139228416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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