Therapeutic advances in rare disease最新文献

{"title":"Therapeutic angiogenesis in Buerger's disease: reviewing the treatment landscape.","authors":"Antoine J Ribieras, Yulexi Y Ortiz, Zhao-Jun Liu, Omaida C Velazquez","doi":"10.1177/26330040211070295","DOIUrl":"10.1177/26330040211070295","url":null,"abstract":"<p><p>Thromboangiitis obliterans, also known as Buerger's disease, is a rare inflammatory vasculitis that predominantly develops in smokers and characteristically affects the small- and medium-sized peripheral arteries and veins. Patients typically present with extremity claudication, but symptoms may progress to rest pain and tissue loss, especially in those unable to abstain from tobacco use. Unfortunately, traditional medical treatments are largely ineffective and due to the small caliber of affected vessels and lack of suitable distal targets or venous conduits, endovascular and open surgical approaches are often not possible. Eventually, a significant number of patients require major amputation. For these reasons, much research effort has been made in developing techniques of therapeutic angiogenesis to improve limb perfusion, both for atherosclerotic peripheral arterial disease and the smaller subset of patients with critical limb ischemia due to Buerger's disease. Neovascularization in response to ischemia relies on a complex interplay between the local tissue microenvironment and circulating stem and progenitor cells. To date, studies of therapeutic angiogenesis have therefore focused on exploiting known angiogenic factors and stem cells to induce neovascularization in ischemic tissues. This review summarizes the available clinical data regarding the safety and efficacy of various angiogenic therapies, notably injection of naked DNA plasmids, viral gene constructs, and cell-based preparations, and describes techniques for potentiating <i>in vivo</i> efficacy of gene- and cell-based therapies as well as ongoing developments in exosome-based cell-free approaches for therapeutic angiogenesis.</p><p><strong>Plain language title and summary: </strong><i>A review of available and emerging treatments for improving blood flow and wound healing in patients with Buerger's disease, a rare disorder of blood vessels</i> Buerger's disease is a rare disorder of the small- and medium-sized blood vessels in the arms and legs that almost exclusively develops in young smokers. Buerger's disease causes inflammation in arteries and veins, which leads to blockage of these vessels and reduces blood flow to and from the extremities. Decreased blood flow to the arms and legs can lead to development of nonhealing wounds and infection for which some patients may eventually require amputation. Unfortunately, traditional medical and surgical treatments are not effective in Buerger's disease, so other methods for improving blood flow are needed for these patients. There are several different ways to stimulate new blood vessel formation, both in humans and animal models. The most common treatments involve injection of DNA or viruses that express genes related to blood vessel formation or, alternatively, stem cell-based treatments that help regenerate blood vessels and repair wound tissue. This review explores how safe and effective these various treatments are and desc","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"3 ","pages":"26330040211070295"},"PeriodicalIF":0.0,"publicationDate":"2022-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7a/81/10.1177_26330040211070295.PMC10032470.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9472955","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}

{"title":"Impact of the Covid-19 epidemic on a US sample of patients with myasthenia gravis.","authors":"Gloria Gutierrez,&nbsp;Helen Girma,&nbsp;Pierce Kuhnell,&nbsp;Maurizio Macaluso,&nbsp;Henry J Kaminski","doi":"10.1177/26330040221082673","DOIUrl":"https://doi.org/10.1177/26330040221082673","url":null,"abstract":"<p><strong>Introduction: </strong>The Covid-19 pandemic has devastated the world and demonstrated the inadequacy of health care in the United States. To assess its impact, the Rare Disease Clinical Research Network conducted a survey to assess the pandemic on the rare disease community of patients, including those with myasthenia gravis (MG).</p><p><strong>Methods: </strong>A cross-sectional survey was designed to target people or their care givers who live in the United States, have a rare disease, and are under 90 years of age. Respondents logged onto a dedicated web page and completed the survey online, which requested demographic, disease-specific, drug treatment, and symptom information as well as assessment of Covid-19 impact on them. The survey was open from May 2020 to December 2020.</p><p><strong>Results: </strong>Five hundred ninety-four with self-reported myasthenia gravis completed the survey, which was the largest number of respondents. Sixty percent of respondents were women with a mean age of 60 years. Eighty-nine percent identified as White. Respondents did not appreciate a worsening of symptoms after the pandemic. Only 7 respondents reported the diagnosis of Covid-19 but 11% indicated they had difficulty accessing care at the time of the survey.</p><p><strong>Discussion and conclusion: </strong>Patients with MG complained of worse access to medical care during the early months of the pandemic, including challenges in diagnosis of suspected Covid-19 infection. A major limitation of the survey is its inability to access minority populations. Nevertheless, the results of the Rare Disease Clinical Research Network (RCDRN) survey of patients with MG provide clear evidence that the pandemic has demonstrated the deficiencies in US healthcare.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"3 ","pages":"26330040221082673"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3e/79/10.1177_26330040221082673.PMC10032427.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9399548","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}

{"title":"Beyond pigmentation: signs of liver protection during afamelanotide treatment in Swiss patients with erythropoietic protoporphyria, an observational study.","authors":"Anna-Elisabeth Minder,&nbsp;Jasmin Barman-Aksoezen,&nbsp;Mathias Schmid,&nbsp;Elisabeth I Minder,&nbsp;Henryk Zulewski,&nbsp;Christoph E Minder,&nbsp;Xiaoye Schneider-Yin","doi":"10.1177/26330040211065453","DOIUrl":"10.1177/26330040211065453","url":null,"abstract":"<p><p>Erythropoietic protoporphyria (EPP) is an ultra-rare inherited disorder with overproduction of protoporphyrin in maturating erythroblasts. This excess protoporphyrin leads to incapacitating phototoxic burns in sunlight exposed skin. Its biliary elimination causes cholestatic liver injury in 20% and terminal liver failure in 4% of EPP patients. Thereby, the risk of liver injury increases with increasing erythrocyte protoporphyrin concentrations. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analog inducing skin pigmentation, was shown to improve sunlight tolerance in EPP. Beyond this well-known effect on pigmentation, the MSHs have liver-protective effects and improve survival of maturating erythroblasts, effects described in animal or <i>in vitro</i> models to date only. We investigated whether afamelanotide treatment in EPP has effects on erythropoiesis, protoporphyrin concentrations, and liver injury by analyzing retrospectively our long-term safety data.</p><p><strong>Methods: </strong>From the 47 Swiss EPP-patients treated at our center since 2006, we included those 38 patients in the current analysis who received at least one afamelanotide dose between 2016 and 2018 and underwent regular laboratory testing before and during the treatment. We compared the means of pretreatment measurements with those during the treatment.</p><p><strong>Results: </strong>Protoporphyrin concentrations dropped from 21.39 ± 11.12 (mean ± SD) before afamelanotide to 16.83 ± 8.24 µmol/L (<i>p</i> < .0001) during treatment. Aspartate aminotransferase decreased from 26.67 ± 13.16 to 22.9 ± 7.76 IU/L (<i>p</i> = .0146). For both entities, patients with higher values showed a more progressive decrease, indicating a risk reduction of EPP-related liver disease. The pre-existing hypochromia and broad mean red-cell distribution width were further augmented under afamelanotide. This was more likely due to an influence of afamelanotide on maturating erythroblasts than due to an exacerbated iron deficiency, as mean zinc-protoporphyrin decreased significantly and ferritin remained unchanged. No serious afamelanotide-related adverse events were observed for a total of 240 treatment years.</p><p><strong>Conclusion: </strong>Our findings point to a protective effect of afamelanotide on erythroblast maturation and protoporphyrin-induced liver injury.</p><p><strong>Plain language summary: </strong><b>Afamelanotide, a skin tanning hormone, may protect patients with erythropoietic protoporphyria not only from skin burns, but also from liver injury associated with the disease.</b> Patients with erythropoietic protoporphyria (EPP), an inherited metabolic disease, suffer from light-induced skin burns and liver injury elicited by the accumulated light sensitizer protoporphyrin. The excess protoporphyrin is produced in red cell precursors in the bone marrow, and it is eliminated from the body <i>via</i> the liver and bile. A high protoporphyrin excretion burden damages th","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211065453"},"PeriodicalIF":0.0,"publicationDate":"2021-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/ca/10.1177_26330040211065453.PMC10032460.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10299665","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}

{"title":"Etranacogene dezaparvovec for hemophilia B gene therapy.","authors":"Courtney D Thornburg","doi":"10.1177/26330040211058896","DOIUrl":"10.1177/26330040211058896","url":null,"abstract":"<p><p>The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211058896"},"PeriodicalIF":0.0,"publicationDate":"2021-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a2/ec/10.1177_26330040211058896.PMC10032433.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9473479","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}

{"title":"Marfan syndrome and the eye clinic: from diagnosis to management.","authors":"Haseeb Akram,&nbsp;Jose Antonio Aragon-Martin,&nbsp;Aman Chandra","doi":"10.1177/26330040211055738","DOIUrl":"10.1177/26330040211055738","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is an autosomal dominantly inherited disorder affecting the cardiovascular, ocular and musculoskeletal systems. Frequently, clinical suspicion and subsequent diagnosis begins in the ophthalmology clinic. Importantly, the ophthalmologist has a responsibility to cater not only to the eye, but also to be involved in a holistic approach for these patients. In this review, we discuss how MFS may present to an eye clinic, including clinical features, ocular morbidity, genetic diagnosis and management. Although this condition is ideally managed by a multidisciplinary team, our focus will be on MFS and the eye, including other conditions which may present with similar phenotypes. The ophthalmologist's role as the potential first contact for a patient with suspected MFS is crucial in making the proper investigations and referral, with the knowledge that not all ectopia lentis cases are MFS and vice versa. Management of ocular conditions in MFS may range from simple observation to surgical intervention; current options will be discussed.</p>","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211055738"},"PeriodicalIF":0.0,"publicationDate":"2021-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/63/d3/10.1177_26330040211055738.PMC10032431.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9473478","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}

{"title":"Improving patient informed consent for haemophilia gene therapy: the case for change.","authors":"Laurence Woollard,&nbsp;Richard Gorman,&nbsp;Dakota J Rosenfelt","doi":"10.1177/26330040211047244","DOIUrl":"10.1177/26330040211047244","url":null,"abstract":"<p><p>Adeno-associated virus-based gene therapy points to a coming transformation in the treatment of people living with haemophilia, promising sustained bleed control and potential improvement in quality of life. Nevertheless, the consequences of introducing new genetic material are not trivial. The perceived benefits should not minimise the challenges facing patients in understanding the long-term risks and providing a valid and meaningful informed consent, whether in a research or clinical setting. Informed consent is a fundamentally important doctrine in both medical ethics and health law, upholding an individual's right to define their personal goals and make their own autonomous choices. Patients should be enabled to recognise their clinical situation, understand the implications of treatment and integrate every facet of their life into their decision. This review describes informed consent processes for haemophilia gene therapy clinical trials, factors affecting patients' decision making and the availability of patient-centred decision support interventions, to ensure that patients' interests are being protected. Regulatory guidance has been published for physicians and manufacturers in haemophilia on informed consent, including for gene therapy, while best-practice recommendations for patient-physician discussions are available. In all settings, however, communicating and presenting highly technical and complex therapeutic information is challenging, especially where multiple barriers to scientific knowledge and health literacy exist. We propose several evidence-informed strategies to enhance the consent procedure, such as utilising validated literacy and knowledge assessment tools as well as participatory learning environments over an extended period, to ensure that patients are fully cognisant of the consent they give or deny. Further research is needed to define new, creative approaches for patient education and the upholding of ethical values in the informed consent process for gene therapy. The lessons learnt and approaches developed within haemophilia could set the gold standard for good practice in ensuring ethical preparedness amidst advances in genetic therapies.</p><p><strong>Plain language summary: </strong><i>Improving the informed consent process for people living with haemophilia considering gene therapy.</i> Gene therapy is the process of replacing faulty genes with healthy ones. In haemophilia, gene therapy involves introducing a working copy of the gene for the clotting factor that patients are missing. Following treatment, patients should begin producing their own clotting factor normally. However, people living with haemophilia (PwH) need to be fully informed regarding the potential benefits and risks of gene therapy and what this means for them, whether as part of a research study or routine medical care.Patients must be respected and supported to make decisions about their own health and wellbeing, recognising their l","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211047244"},"PeriodicalIF":0.0,"publicationDate":"2021-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/de/62/10.1177_26330040211047244.PMC10032461.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9839547","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}

{"title":"Utilizing telehealth to create a clinical model of care for patients with Batten disease and other rare diseases.","authors":"Jessica F Scherr,&nbsp;Charles Albright,&nbsp;Emily de Los Reyes","doi":"10.1177/26330040211038564","DOIUrl":"10.1177/26330040211038564","url":null,"abstract":"<p><p>The COVID-19 pandemic transformed the delivery of healthcare across the world. Telehealth has emerged as the primary method for providing healthcare early in the pandemic. Patient and healthcare provider views of the effectiveness of telehealth services are encouraging and support the long-term use of telehealth services in clinical practice. Telehealth may provide a strategy that has far-reaching benefits for diverse patient populations, such as patients with Batten disease and other rare diseases, who face additional barriers to accessing subspecialty healthcare services. The aims of this paper, through the experience of a single Batten Disease Center of Excellence, are to (1) review the benefits and barriers involved in the delivery of telehealth services to patients with rare diseases; (2) discuss components of a model for clinical care that utilizes telehealth services for patients with Batten disease; (3) discuss limitations and future directions of using telehealth in patients with rare diseases. Healthcare systems should consider building clinical models that utilize telehealth services to provide multidisciplinary services to patients with rare diseases. There are numerous benefits in using telehealth that can enhance and expand service delivery between the patient and clinician. Telehealth services can also improve provider-to-provider communication and collaboration when providing clinical care to individuals with rare diseases. Although there are many benefits to utilizing telehealth services in provision of care to patients with rare diseases, it is important to consider factors that may limit or add additional barriers prior to implementing telehealth services. There is a need for future collaborative research to examine and compare the effectiveness and outcomes of telehealth services with standard of care services that are provided in-person. Future research should also examine how to reduce the challenges and barriers associated with the implementation of telehealth services.</p><p><strong>Plain language summary: </strong><b>What is telehealth?</b> Telehealth is defined by the US Department of Health Resources and Services Administrations¹ as the \"use of electronic information and telecommunication technologies to support long-distance clinical healthcare, patient and professional health-related education, public health, and health administration. Technologies include video conference, the internet, store-and-forward imaging, streaming media, and terrestrial and wireless communication.\" <b>What was the aim of this review?</b> This review was conducted to guide a clinical model using telehealth services for patients with Batten disease and other rare diseases based on the experiences of a single Batten Disease Center of Excellence. <b>Why is this important?</b> Individuals with rare diseases may face multiple barriers to accessing clinical services. Local doctors and treatment providers, such as speech therapists,","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211038564"},"PeriodicalIF":0.0,"publicationDate":"2021-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/85/10.1177_26330040211038564.PMC10032454.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9468603","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}

{"title":"Wolfram syndrome: new pathophysiological insights and therapeutic strategies.","authors":"Ratnakar Mishra,&nbsp;Benson S Chen,&nbsp;Prachi Richa,&nbsp;Patrick Yu-Wai-Man","doi":"10.1177/26330040211039518","DOIUrl":"10.1177/26330040211039518","url":null,"abstract":"<p><p>Wolfram Syndrome (WS) is an ultra-rare, progressive neurodegenerative disease characterized by early-onset diabetes mellitus and irreversible loss of vision, secondary to optic nerve degeneration. Visual loss in WS is an important cause of registrable blindness in children and young adults and the pathological hallmark is the preferential loss of retinal ganglion cells within the inner retina. In addition to optic atrophy, affected individuals frequently develop variable combinations of neurological, endocrinological, and psychiatric complications. The majority of patients carry recessive mutations in the <i>WFS1</i> (4p16.1) gene that encodes for a multimeric transmembrane protein, wolframin, embedded within the endoplasmic reticulum (ER). An increasingly recognised subgroup of patients harbor dominant <i>WFS1</i> mutations that usually cause a milder phenotype, which can be limited to optic atrophy. Wolframin is a ubiquitous protein with high levels of expression in retinal, neuronal, and muscle tissues. It is a multifunctional protein that regulates a host of cellular functions, in particular the dynamic interaction with mitochondria at mitochondria-associated membranes. Wolframin has been implicated in several crucial cellular signaling pathways, including insulin signaling, calcium homeostasis, and the regulation of apoptosis and the ER stress response. There is currently no cure for WS; management remains largely supportive. This review will cover the clinical, genetic, and pathophysiological features of WS, with a specific focus on disease models and the molecular pathways that could serve as potential therapeutic targets. The current landscape of therapeutic options will also be discussed in the context of the latest evidence, including the pipeline for repurposed drugs and gene therapy.</p><p><strong>Plain language summary: </strong><b>Wolfram syndrome - disease mechanisms and treatment options</b> Wolfram syndrome (WS) is an ultra-rare genetic disease that causes diabetes mellitus and progressive loss of vision from early childhood. Vision is affected in WS because of damage to a specialized type of cells in the retina, known as retinal ganglion cells (RGCs), which converge at the back of the eye to form the optic nerve. The optic nerve is the fast-conducting cable that transmits visual information from the eye to the vision processing centers within the brain. As RGCs are lost, the optic nerve degenerates and it becomes pale in appearance (optic atrophy). Although diabetes mellitus and optic atrophy are the main features of WS, some patients can develop more severe problems because the brain and other organs, such as the kidneys and the bladder, are also affected. The majority of patients with WS carry spelling mistakes (mutations) in the <i>WFS1</i> gene, which is located on the short arm of chromosome 4 (4p16.1). This gene is highly expressed in the eye and in the brain, and it encodes for a protein located within a compartment","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211039518"},"PeriodicalIF":0.0,"publicationDate":"2021-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6b/ac/10.1177_26330040211039518.PMC10032446.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9473480","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}

{"title":"New avenues for therapy in mitochondrial optic neuropathies.","authors":"Wing Sum Vincent Ng,&nbsp;Matthieu Trigano,&nbsp;Thomas Freeman,&nbsp;Carmine Varrichio,&nbsp;Dinesh Kumar Kandaswamy,&nbsp;Ben Newland,&nbsp;Andrea Brancale,&nbsp;Malgorzata Rozanowska,&nbsp;Marcela Votruba","doi":"10.1177/26330040211029037","DOIUrl":"10.1177/26330040211029037","url":null,"abstract":"<p><p>Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.</p><p><strong>Plain language summary: </strong>Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for th","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211029037"},"PeriodicalIF":0.0,"publicationDate":"2021-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/26330040211029037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9468608","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}

{"title":"Enzyme replacement therapy in lysosomal acid lipase deficiency (LAL-D): a systematic literature review.","authors":"Aamir Bashir,&nbsp;Pramil Tiwari,&nbsp;Ajay Duseja","doi":"10.1177/26330040211026928","DOIUrl":"10.1177/26330040211026928","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal acid lipase deficiency (LAL-D) is a very rare genetic abnormality caused by LIPA gene mutation. The disease has two distinct clinical variants in humans: Wolman disease in infants and cholesteryl ester storage disease in children and adults. Both conditions are characterized by elevated serum transaminases, dyslipidaemia, severe liver steatosis and accelerated fibrosis or cirrhosis, contributing to its high rate of early mortality. Recently sebelipase alfa (recombinant human LAL) was launched to address its underlying pathology. This systematic review evaluates the safety and efficacy of sebelipase alfa for LAL-D.</p><p><strong>Methods: </strong>This systematic review was performed following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical trial records were systematically searched in <i>PubMed/Medline</i>, <i>ClinicalTrials.gov., Cochrane Library</i> and <i>Google Scholar</i> up to September 2020. Records that have reported at least one of the included outcomes were included. Baseline and endpoint mean and standard deviation (SD) for all outcomes were recorded. For safety, frequency and overall distribution of different adverse events were included.</p><p><strong>Results: </strong>A total of seven records from five individual studies with 110 LAL-D patients were included into this study. The mean age ranged from 2.57 months in infants to 31.6 years among adults. Serum transaminases (alanine aminotransferase and aspartate aminotransferase), serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol), gamma-glutamyl transferase and liver volume were included as efficacy outcomes. Final pooled results were synthesized as a change from baseline to end of the treatment. A significant effect on both serum transaminases and other serum lipid was achieved (<i>p</i> < 0.01), while non-significant differences were seen for GGT and liver volume as <i>p</i> = 0.35 and <i>p</i> = 0.08 was observed. Mostly the adverse events related to the infusions were infrequent and mild-to-moderate in severity.</p><p><strong>Conclusion: </strong>Sebelipase alfa as an enzyme replacement provides an effective, safe and well tolerated treatment in both variants of LAL-D.</p><p><strong>Plain language summary: </strong><b>A systematic literature review on safety and efficacy of enzyme replacement therapy in lysosomal acid lipase deficiency</b> Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, genetic disorder caused by functional mutations in the LIPA gene, which encodes LAL enzyme. This enzyme maintains lipid homeostasis by hydrolysing the cholesterol esters and triglycerides. Patients with deficient LAL activity are seen with abnormal liver functions which keep them at a high risk of early mortality. Clinical diagnosis of this disease is very challenging due to both its low prevalence and low awareness among ","PeriodicalId":75218,"journal":{"name":"Therapeutic advances in rare disease","volume":"2 ","pages":"26330040211026928"},"PeriodicalIF":0.0,"publicationDate":"2021-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/26330040211026928","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9468607","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}