Pub Date : 2021-01-02DOI: 10.1080/21678707.2021.1882299
G. Sgalla, Marialessia Lerede, L. Richeldi
ABSTRACT Introduction The last two decades witnessed an increasing number of well-designed late phase trials in patients with Idiopathic Pulmonary Fibrosis (IPF), leading to the approval of the first effective therapies for these patients, pirfenidone and nintedanib. Currently, novel putative agents for the treatment of IPF are being tested in phase III trials, possibly marking a new breakthrough in IPF management. Areas covered In this review, the available evidence on completed phase III trials in IPF is summarized, from the past failures of immunosuppressive and anti-inflammatory agents, anticoagulants and endothelin-receptor antagonists to the positive results of the antifibrotic treatments that revolutionized IPF therapeutic landscape. Literature search was performed using Medline and Clinicaltrials.org databases (1999–2020). Expert opinion In the relatively young history of pharmaceutical research in IPF, most phase III trials provided disappointing results, however the lessons learned helped paving the way to the success of the first therapies capable of modifying the natural history of this deadly disease. To date, the conduction of robustly designed phase III trials on novel drugs remains crucial to pursue the goal of halting disease progression in these patients, using a therapeutic approach that should become more and more tailored to the individual.
{"title":"Phase three clinical trials in idiopathic pulmonary fibrosis","authors":"G. Sgalla, Marialessia Lerede, L. Richeldi","doi":"10.1080/21678707.2021.1882299","DOIUrl":"https://doi.org/10.1080/21678707.2021.1882299","url":null,"abstract":"ABSTRACT Introduction The last two decades witnessed an increasing number of well-designed late phase trials in patients with Idiopathic Pulmonary Fibrosis (IPF), leading to the approval of the first effective therapies for these patients, pirfenidone and nintedanib. Currently, novel putative agents for the treatment of IPF are being tested in phase III trials, possibly marking a new breakthrough in IPF management. Areas covered In this review, the available evidence on completed phase III trials in IPF is summarized, from the past failures of immunosuppressive and anti-inflammatory agents, anticoagulants and endothelin-receptor antagonists to the positive results of the antifibrotic treatments that revolutionized IPF therapeutic landscape. Literature search was performed using Medline and Clinicaltrials.org databases (1999–2020). Expert opinion In the relatively young history of pharmaceutical research in IPF, most phase III trials provided disappointing results, however the lessons learned helped paving the way to the success of the first therapies capable of modifying the natural history of this deadly disease. To date, the conduction of robustly designed phase III trials on novel drugs remains crucial to pursue the goal of halting disease progression in these patients, using a therapeutic approach that should become more and more tailored to the individual.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"1 - 11"},"PeriodicalIF":0.8,"publicationDate":"2021-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2021.1882299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42626087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-02DOI: 10.1080/21678707.2021.1882994
K. Hong, M. Brambatti, S. John, Q. Bui, M. Rigolli, Matthew R. G. Taylor, E. Adler
ABSTRACT Introduction: Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy where phenotypic expression varies by sex. It is characterized by severe cardiomyopathy, skeletal myopathy, and cognitive impairment, but can include retinopathy, gastrointestinal, hepatic and pulmonary manifestations. Areas covered: This review of DD will cover genetics, pathophysiologic mechanisms, clinical characteristics and diagnostics, and management, and synthesizes Danon Disease literature found In PubMed from 2000 to the present. Clinical reviews, outcomes studies, registry data, case series and mechanistic studies and chapters were reviewed. Expert opinion: DD is caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene which is involved in autophagy. Diagnosis is aided by an x-linked hereditary pattern coupled with clinical history suggesting a cardiomyopathy with multi-organ dysfunction, neurocognitive deficits, myopathy and visual defects. Current treatment trials in DD are lacking and therapeutic decisions are extrapolated from guidelines for hypertrophic and dilated cardiomyopathies. The efficacy of these treatments as well as therapies specific to DD are important areas for research. Natural history studies that can inform therapeutic trial design as well as comparative effectiveness research specific to DD and other cardiomyopathies can bridge critical knowledge gaps in DD therapies.
{"title":"Recommendations and guidance on the diagnosis and management of Danon disease","authors":"K. Hong, M. Brambatti, S. John, Q. Bui, M. Rigolli, Matthew R. G. Taylor, E. Adler","doi":"10.1080/21678707.2021.1882994","DOIUrl":"https://doi.org/10.1080/21678707.2021.1882994","url":null,"abstract":"ABSTRACT Introduction: Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy where phenotypic expression varies by sex. It is characterized by severe cardiomyopathy, skeletal myopathy, and cognitive impairment, but can include retinopathy, gastrointestinal, hepatic and pulmonary manifestations. Areas covered: This review of DD will cover genetics, pathophysiologic mechanisms, clinical characteristics and diagnostics, and management, and synthesizes Danon Disease literature found In PubMed from 2000 to the present. Clinical reviews, outcomes studies, registry data, case series and mechanistic studies and chapters were reviewed. Expert opinion: DD is caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene which is involved in autophagy. Diagnosis is aided by an x-linked hereditary pattern coupled with clinical history suggesting a cardiomyopathy with multi-organ dysfunction, neurocognitive deficits, myopathy and visual defects. Current treatment trials in DD are lacking and therapeutic decisions are extrapolated from guidelines for hypertrophic and dilated cardiomyopathies. The efficacy of these treatments as well as therapies specific to DD are important areas for research. Natural history studies that can inform therapeutic trial design as well as comparative effectiveness research specific to DD and other cardiomyopathies can bridge critical knowledge gaps in DD therapies.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"25 - 33"},"PeriodicalIF":0.8,"publicationDate":"2021-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2021.1882994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44507933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-03-24DOI: 10.1080/21678707.2021.1882300
Ruofan Connie Han, Lewis E Fry, Ariel Kantor, Michelle E McClements, Kanmin Xue, Robert E MacLaren
Introduction: Choroideremia is an X-linked inherited retinal degeneration resulting from mutations in the CHM gene, encoding Rab escort protein-1 (REP1), a protein regulating intracellular vesicular transport. Loss-of-function mutations in CHM lead to progressive loss of retinal pigment epithelium (RPE) with photoreceptor and choriocapillaris degeneration, leading to progressive visual field constriction and loss of visual acuity. Three hundred and fifty-four unique mutations have been reported in CHM. While gene augmentation remains an ideal therapeutic option for choroideremia, other potential future clinical strategies may exist.
Areas covered: The authors examine the pathophysiology and genetic basis of choroideremia. They summarize the status of ongoing gene therapy trials and discuss CHM mutations amenable to other therapeutic approaches including CRISPR/Cas-based DNA and RNA editing, nonsense suppression of premature termination codons, and antisense oligonucleotides for splice modification. The authors undertook a literature search in PubMed and NIH Clinical Trials in October 2020.
Expert opinion: The authors conclude that AAV-mediated gene augmentation remains the most effective approach for choroideremia. Given the heterogeneity of CHM mutations and potential risks and benefits, genome-editing approaches currently do not offer significant advantages. Nonsense suppression strategies and antisense oligonucleotides are exciting novel therapeutic options; however, their clinical viability remains to be determined.
{"title":"Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?","authors":"Ruofan Connie Han, Lewis E Fry, Ariel Kantor, Michelle E McClements, Kanmin Xue, Robert E MacLaren","doi":"10.1080/21678707.2021.1882300","DOIUrl":"10.1080/21678707.2021.1882300","url":null,"abstract":"<p><strong>Introduction: </strong>Choroideremia is an X-linked inherited retinal degeneration resulting from mutations in the <i>CHM</i> gene, encoding Rab escort protein-1 (REP1), a protein regulating intracellular vesicular transport. Loss-of-function mutations in <i>CHM</i> lead to progressive loss of retinal pigment epithelium (RPE) with photoreceptor and choriocapillaris degeneration, leading to progressive visual field constriction and loss of visual acuity. Three hundred and fifty-four unique mutations have been reported in <i>CHM.</i> While gene augmentation remains an ideal therapeutic option for choroideremia, other potential future clinical strategies may exist.</p><p><strong>Areas covered: </strong>The authors examine the pathophysiology and genetic basis of choroideremia. They summarize the status of ongoing gene therapy trials and discuss <i>CHM</i> mutations amenable to other therapeutic approaches including CRISPR/Cas-based DNA and RNA editing, nonsense suppression of premature termination codons, and antisense oligonucleotides for splice modification. The authors undertook a literature search in PubMed and NIH Clinical Trials in October 2020.</p><p><strong>Expert opinion: </strong>The authors conclude that AAV-mediated gene augmentation remains the most effective approach for choroideremia. Given the heterogeneity of <i>CHM</i> mutations and potential risks and benefits, genome-editing approaches currently do not offer significant advantages. Nonsense suppression strategies and antisense oligonucleotides are exciting novel therapeutic options; however, their clinical viability remains to be determined.</p>","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"9 1","pages":"13-24"},"PeriodicalIF":0.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c2/ff/EMS123013.PMC7610829.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39023192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-12-01DOI: 10.1080/21678707.2020.1865918
Abhinav Kumar, J. Rocke, B. Kumar
ABSTRACT Introduction: Neuroblastoma is a tumor of the developing sympathetic nervous system. Low and intermediate-risk patients usually have good treatment outcomes, whereas high-risk cases have poorer survival and recurrence rates. This review highlights limitations in the treatment procedure and future therapies in development that may be adopted into clinical practice, compiled from a literature search of scientific papers from the last 30 years including ongoing clinical trials. Areas covered: Current treatments for high-risk neuroblastoma have shown efficacy in clinical trials; however, this regimen is not effective in preventing relapse in many cases and has high toxicity for pediatric patients. The two main areas of research for new maintenance therapies focus on immunotherapy and gene targeting with molecular therapy. GD2-CAR-T cells and GD2 vaccines have shown efficacy in pre-clinical trials, and MYCN and ALK inhibition target two of the main driver mutations in neuroblastoma potentially offering a highly specific form of therapy. Expert opinion: Tumor heterogeneity leads to various drivers of neuroblastoma; therefore, combinations of molecular therapies can induce remission, alongside immunotherapy that could lower treatment toxicity. The implementation of ‘liquid biopsies’ could greatly improve genetic characterization of a changing tumor profile (often changing in response to treatment) to inform appropriate therapies.
摘要:神经母细胞瘤是发生在交感神经系统的一种肿瘤。低、中危患者通常具有良好的治疗效果，而高危患者的生存率和复发率较差。本综述通过对过去30年的科学论文(包括正在进行的临床试验)的文献检索，强调了治疗程序的局限性和正在开发的可能用于临床实践的未来疗法。涵盖领域:目前高危神经母细胞瘤的治疗方法已在临床试验中显示出疗效;然而，在许多情况下，这种方案在预防复发方面并不有效，并且对儿科患者具有高毒性。新的维持疗法研究的两个主要领域集中在免疫疗法和基因靶向分子疗法。GD2- car - t细胞和GD2疫苗在临床前试验中显示出疗效，MYCN和ALK抑制靶向神经母细胞瘤的两种主要驱动突变，可能提供一种高度特异性的治疗形式。专家意见:肿瘤异质性导致神经母细胞瘤的各种驱动因素;因此，结合分子疗法可以诱导缓解，同时免疫疗法可以降低治疗毒性。实施“液体活检”可以极大地改善变化的肿瘤特征的遗传特征(通常因治疗而变化)，从而为适当的治疗提供信息。
{"title":"Evolving treatments in high-risk neuroblastoma","authors":"Abhinav Kumar, J. Rocke, B. Kumar","doi":"10.1080/21678707.2020.1865918","DOIUrl":"https://doi.org/10.1080/21678707.2020.1865918","url":null,"abstract":"ABSTRACT Introduction: Neuroblastoma is a tumor of the developing sympathetic nervous system. Low and intermediate-risk patients usually have good treatment outcomes, whereas high-risk cases have poorer survival and recurrence rates. This review highlights limitations in the treatment procedure and future therapies in development that may be adopted into clinical practice, compiled from a literature search of scientific papers from the last 30 years including ongoing clinical trials. Areas covered: Current treatments for high-risk neuroblastoma have shown efficacy in clinical trials; however, this regimen is not effective in preventing relapse in many cases and has high toxicity for pediatric patients. The two main areas of research for new maintenance therapies focus on immunotherapy and gene targeting with molecular therapy. GD2-CAR-T cells and GD2 vaccines have shown efficacy in pre-clinical trials, and MYCN and ALK inhibition target two of the main driver mutations in neuroblastoma potentially offering a highly specific form of therapy. Expert opinion: Tumor heterogeneity leads to various drivers of neuroblastoma; therefore, combinations of molecular therapies can induce remission, alongside immunotherapy that could lower treatment toxicity. The implementation of ‘liquid biopsies’ could greatly improve genetic characterization of a changing tumor profile (often changing in response to treatment) to inform appropriate therapies.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"8 1","pages":"497 - 506"},"PeriodicalIF":0.8,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2020.1865918","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46712807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-12-01DOI: 10.1080/21678707.2020.1865917
A. Floreani, S. De Martin, T. Ikeura, K. Okazaki, M. Gershwin
ABSTRACT Introduction: Microbial antigens present in the intestine has been suggested as possible triggers of primary biliary cholangitis (PBC) and it has been demonstrated that the gut microbiome is modified in PBC patients. On this basis, the modulation of the gut microbiome has been proposed as a pharmacological target for PBC management. To provide a state-of-the-art analysis of the preclinical and clinical evidence on this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 2000–2020). Area covered: In particular, several strategies for microbiome modulation have been investigated in both experimental and clinical studies, i.e. dietary interventions, and the administration of probiotics and prebiotics and drugs. Moreover, clinical evidence point to two drugs approved for PBC, i.e. ursodeoxycholic and obeticholic acids, as gut flora modulators. Accordingly, fecal microbiota transplantation is also under evaluation for PBC treatment. On the other hand, typical alterations of the microbiome have been observed in PBC patients, although their diagnostic impact remains to be better evaluated. Expert opinion: The addition of gut microbiome manipulation to standard pharmacological treatments is one important challenge for PBC therapy in the near future. Further studies are needed to ascertain whether microbiome profiling could be considered a diagnostic strategy in PBC.
{"title":"Gut microbial profiling as a therapeutic and diagnostic target for managing primary biliary cholangitis.","authors":"A. Floreani, S. De Martin, T. Ikeura, K. Okazaki, M. Gershwin","doi":"10.1080/21678707.2020.1865917","DOIUrl":"https://doi.org/10.1080/21678707.2020.1865917","url":null,"abstract":"ABSTRACT Introduction: Microbial antigens present in the intestine has been suggested as possible triggers of primary biliary cholangitis (PBC) and it has been demonstrated that the gut microbiome is modified in PBC patients. On this basis, the modulation of the gut microbiome has been proposed as a pharmacological target for PBC management. To provide a state-of-the-art analysis of the preclinical and clinical evidence on this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 2000–2020). Area covered: In particular, several strategies for microbiome modulation have been investigated in both experimental and clinical studies, i.e. dietary interventions, and the administration of probiotics and prebiotics and drugs. Moreover, clinical evidence point to two drugs approved for PBC, i.e. ursodeoxycholic and obeticholic acids, as gut flora modulators. Accordingly, fecal microbiota transplantation is also under evaluation for PBC treatment. On the other hand, typical alterations of the microbiome have been observed in PBC patients, although their diagnostic impact remains to be better evaluated. Expert opinion: The addition of gut microbiome manipulation to standard pharmacological treatments is one important challenge for PBC therapy in the near future. Further studies are needed to ascertain whether microbiome profiling could be considered a diagnostic strategy in PBC.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"8 1","pages":"507 - 514"},"PeriodicalIF":0.8,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2020.1865917","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41982815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-12-01DOI: 10.1080/21678707.2020.1865916
C. Angelini, V. Pegoraro
ABSTRACT Introduction: Sarcoglycanopathies (SG) are caused by a mutation in SGCA, SGCB, SGCG, or SGCD genes and present a wide spectrum of muscle involvement and wasting. The clinical phenotypes due to a mutation in the sarcoglycan genes include severe childhood-onset forms, proximal myopathies, pseudometabolic myopathies, myopathies with respiratory complication, and hyperCKemia syndromes. Dilated cardiomyopathy is more frequent and severe in LGMD2E/R4 and LGMD2F/R6. Areas covered: In this paper, the authors review clinical, epidemiological evidence-based studies for better understanding the clinical signs, natural history and provide an update on current diagnostic and therapeutic options linked to the management of respiratory insufficiency present in 26% of the cases and cardiac complications present in 22% of the cases, as well as physiotherapy/rehabilitation and drug treatment. We also briefly over-view new treatments specific to genetic mutations and clinical trials on gene therapy. The papers covering the diagnosis and clinical respiratory care and cardiac complications of sarcoglycanopathies were reviewed in PubMed since the year 1997 and we chose to analyze those that covered series of patients, animal studies were only annotated when relevant to pathophysiology or advances in treatment. Expert opinion: Accurate molecular diagnosis of sarcoglycanopathy patients is crucial in order to offer precise genetic counseling and clinical care, both to offer effective management and to prevent cardiac insufficiency. It is important both for an early treatment of dilated cardiomyopathy and to prevent severe respiratory complications in specific subgroups of patients.
{"title":"Assessing diagnosis and managing respiratory and cardiac complications of sarcoglycanopathy","authors":"C. Angelini, V. Pegoraro","doi":"10.1080/21678707.2020.1865916","DOIUrl":"https://doi.org/10.1080/21678707.2020.1865916","url":null,"abstract":"ABSTRACT Introduction: Sarcoglycanopathies (SG) are caused by a mutation in SGCA, SGCB, SGCG, or SGCD genes and present a wide spectrum of muscle involvement and wasting. The clinical phenotypes due to a mutation in the sarcoglycan genes include severe childhood-onset forms, proximal myopathies, pseudometabolic myopathies, myopathies with respiratory complication, and hyperCKemia syndromes. Dilated cardiomyopathy is more frequent and severe in LGMD2E/R4 and LGMD2F/R6. Areas covered: In this paper, the authors review clinical, epidemiological evidence-based studies for better understanding the clinical signs, natural history and provide an update on current diagnostic and therapeutic options linked to the management of respiratory insufficiency present in 26% of the cases and cardiac complications present in 22% of the cases, as well as physiotherapy/rehabilitation and drug treatment. We also briefly over-view new treatments specific to genetic mutations and clinical trials on gene therapy. The papers covering the diagnosis and clinical respiratory care and cardiac complications of sarcoglycanopathies were reviewed in PubMed since the year 1997 and we chose to analyze those that covered series of patients, animal studies were only annotated when relevant to pathophysiology or advances in treatment. Expert opinion: Accurate molecular diagnosis of sarcoglycanopathy patients is crucial in order to offer precise genetic counseling and clinical care, both to offer effective management and to prevent cardiac insufficiency. It is important both for an early treatment of dilated cardiomyopathy and to prevent severe respiratory complications in specific subgroups of patients.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"8 1","pages":"515 - 523"},"PeriodicalIF":0.8,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2020.1865916","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42843497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-12-01DOI: 10.1080/21678707.2020.1865915
S. Shetty, Fahad M. S. Arattu Thodika, A. Greenough
ABSTRACT Introduction: Congenital diaphragmatic hernia (CDH) is one of the most challenging neonatal surgical conditions due to its high mortality and morbidity. A multidisciplinary approach is required regarding the management of affected infants, before birth, during their initial hospitalization and in their long-term follow-up. Areas covered: This review discusses the monitoring and management strategies for infants with CDH including during the prenatal and postnatal periods. It emphasizes the long-term sequelae these patients can suffer throughout childhood and adulthood. This article highlights the progress that has been made and where future developments have the potential to improve the outcome of this vulnerable patient population. A literature search was performed using Google Scholar, Science Direct and PubMed. Expert opinion: Advances in antenatal and neonatal care have improved the early survival of infants with CDH, but many infants are surviving with long-term morbidity. An increasing number of CDH survivors are now reaching adolescence and adulthood. New challenges arise regarding the prevention and management of their long-term problems.
{"title":"Managing respiratory complications in infants and newborns with congenital diaphragmatic hernia","authors":"S. Shetty, Fahad M. S. Arattu Thodika, A. Greenough","doi":"10.1080/21678707.2020.1865915","DOIUrl":"https://doi.org/10.1080/21678707.2020.1865915","url":null,"abstract":"ABSTRACT Introduction: Congenital diaphragmatic hernia (CDH) is one of the most challenging neonatal surgical conditions due to its high mortality and morbidity. A multidisciplinary approach is required regarding the management of affected infants, before birth, during their initial hospitalization and in their long-term follow-up. Areas covered: This review discusses the monitoring and management strategies for infants with CDH including during the prenatal and postnatal periods. It emphasizes the long-term sequelae these patients can suffer throughout childhood and adulthood. This article highlights the progress that has been made and where future developments have the potential to improve the outcome of this vulnerable patient population. A literature search was performed using Google Scholar, Science Direct and PubMed. Expert opinion: Advances in antenatal and neonatal care have improved the early survival of infants with CDH, but many infants are surviving with long-term morbidity. An increasing number of CDH survivors are now reaching adolescence and adulthood. New challenges arise regarding the prevention and management of their long-term problems.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"8 1","pages":"525 - 537"},"PeriodicalIF":0.8,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2020.1865915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48654089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-11-01DOI: 10.1080/21678707.2020.1850254
Nadia Turton, T. Rutherford, D. Thijssen, I. Hargreaves
ABSTRACT Introduction: Oxidative stress (OS) and mitochondrial dysfunction are implicated in the pathogenesis of a number of metabolic diseases. OS occurs when there is an imbalance between the pro-oxidant/antioxidant homeostasis, leading to an increased generation of reactive oxidant species (ROS) with resultant cellular dysfunction. It is becoming apparent that increased ROS generation may be attributable to secondary mitochondrial dysfunction as a consequence of disease pathophysiology. Mitochondrial dysfunction occurs as a result of oxidative damage from enhanced ROS generation as well as the accumulation of toxic metabolites in some metabolic diseases. Areas covered: The present review will discuss evidence of OS and mitochondrial dysfunction in phenylketonuria (PKU), lysosomal storage disorders (LSDs), and peroxisomal disorders. In addition, potential adjunct therapies which have the potential to enhance mitochondrial functioning and mitigate OS will be explored. The databases utilized for this review were Pubmed and the Wed of science, with inclusive dates, 1988–2020. Expert opinion: There is an un-unified approach in the treatment of metabolic diseases. Agents including augmenters of mitochondrial function, antioxidants, and activators of mitochondrial biogenesis, may be beneficial. However, although successful in some cases, these adjunct therapies have yet to be incorporated into the clinical-management of metabolic diseases.
{"title":"Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders","authors":"Nadia Turton, T. Rutherford, D. Thijssen, I. Hargreaves","doi":"10.1080/21678707.2020.1850254","DOIUrl":"https://doi.org/10.1080/21678707.2020.1850254","url":null,"abstract":"ABSTRACT Introduction: Oxidative stress (OS) and mitochondrial dysfunction are implicated in the pathogenesis of a number of metabolic diseases. OS occurs when there is an imbalance between the pro-oxidant/antioxidant homeostasis, leading to an increased generation of reactive oxidant species (ROS) with resultant cellular dysfunction. It is becoming apparent that increased ROS generation may be attributable to secondary mitochondrial dysfunction as a consequence of disease pathophysiology. Mitochondrial dysfunction occurs as a result of oxidative damage from enhanced ROS generation as well as the accumulation of toxic metabolites in some metabolic diseases. Areas covered: The present review will discuss evidence of OS and mitochondrial dysfunction in phenylketonuria (PKU), lysosomal storage disorders (LSDs), and peroxisomal disorders. In addition, potential adjunct therapies which have the potential to enhance mitochondrial functioning and mitigate OS will be explored. The databases utilized for this review were Pubmed and the Wed of science, with inclusive dates, 1988–2020. Expert opinion: There is an un-unified approach in the treatment of metabolic diseases. Agents including augmenters of mitochondrial function, antioxidants, and activators of mitochondrial biogenesis, may be beneficial. However, although successful in some cases, these adjunct therapies have yet to be incorporated into the clinical-management of metabolic diseases.","PeriodicalId":12118,"journal":{"name":"Expert Opinion on Orphan Drugs","volume":"8 1","pages":"431 - 444"},"PeriodicalIF":0.8,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678707.2020.1850254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42239288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-11-01DOI: 10.1080/21678707.2020.1857724
E. Petrova, A. Hovnanian
ABSTRACT Introduction: Netherton syndrome (NS) is a rare and severe ichthyosis characterized by superficial scaling, skin inflammation, a specific hair shaft defect, severe atopic manifestations and multisystemic complications. It is an orphan disease with currently no satisfactory treatment. NS is caused by loss-of-function mutations in SPINK5 encoding the serine protease inhibitor LEKTI. NS patients present with ichthyosiform erythroderma or ichthyosis linearis circumflexa and show considerable clinical variability. Areas covered: Uncontrolled serine protease activity leads to a profound skin barrier defect and the release of pro-inflammatory and pro-allergic mediators by keratinocytes and immune cells. Improved understanding of NS pathogenesis has led to the successful use of repurposed biologics such as intravenous immunoglobulins and anti-IL-17A blockers. Between April 1, 2020 and November 18, 2020, authors searched for NS-relevant information in the following databases: MEDLINE, DrugBank, ClinicalTrials.gov, and patent datasets accessed through lens.org. Expert opinion: Specific KLK5 and/or KLK7 inhibitors represent the most promising disease-modifying treatments. They are currently being developed by several companies. Comprehension of the determinants of NS variability, flares and modification over time will be the foundation for precision medicine. While improved knowledge of the inflammatory and allergic pathways involved is still needed, clinical trials using repurposed biologics have already begun.
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Pub Date : 2020-11-01DOI: 10.1080/21678707.2020.1856654
Shawn C Aylward, J. Pindrik, J. Pindrik, Nicolas J. Abreu, W. B. Cherny, Matthew O'Neal, E. Reyes
ABSTRACT Introduction: Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare, lysosomal storage disease that causes progressive neurodegeneration in children. Cerliponase alfa enzyme replacement therapy is the first approved treatment for CLN2. Areas covered: This article reviews the clinical presentation of CLN2, significant preclinical and clinical studies related to the approvals of cerliponase alfa enzyme replacement therapy (ERT) and other future disease modifying therapies like gene transfer. Authors also describe standard and novel surgical approaches and practical infusion considerations. Authors performed a comprehensive literature review using PubMed and ISI web of science. Inclusive dates of search were from September to October 2020. Expert opinion: Prior to the approval of cerliponase alfa ERT, treatment was limited to symptomatic and palliative approaches. Cerliponase alfa intracerebroventricular therapy offers a safe and effective treatment option with long-term delay of disease progression. Current research indicates treated children have better outcomes in comparison to their natural history counterparts allowing preserved ambulation and language. Future research should be directed toward the discovery of therapies that may allow the delivery or promote production of functional CLN2 protein such as gene therapy.
摘要简介:2型神经性蜡样脂褐质病(CLN2)是一种罕见的溶酶体贮积性疾病，可导致儿童进行性神经变性。Cerliponase alfa酶替代疗法是首个被批准的CLN2治疗方法。涵盖领域:本文回顾了CLN2的临床表现，与批准cerliponase alfa酶替代疗法(ERT)和其他未来疾病修饰疗法(如基因转移)相关的重要临床前和临床研究。作者还描述了标准和新颖的手术方法和实际输液的考虑。作者使用PubMed和ISI web of science进行了全面的文献综述。包括搜索日期为2020年9月至10月。专家意见:在批准cerliponase alfa ERT之前，治疗仅限于对症和姑息性方法。脑室内治疗提供了一种安全有效的治疗选择，可长期延缓疾病进展。目前的研究表明，与自然历史的孩子相比，接受治疗的孩子有更好的结果，允许保留行走和语言。未来的研究应着眼于发现可能允许递送或促进功能性CLN2蛋白产生的治疗方法，如基因治疗。
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