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Gene therapy for inherited metabolic diseases.
Yilmaz, BS, Gurung, S, Perocheau, D, Counsell, J, Baruteau, J
Journal of mother and child. 2020;(2):53-64
Abstract
Over the last two decades, gene therapy has been successfully translated to many rare diseases. The number of clinical trials is rapidly expanding and some gene therapy products have now received market authorisation in the western world. Inherited metabolic diseases (IMD) are orphan diseases frequently associated with a severe debilitating phenotype with limited therapeutic perspective. Gene therapy is progressively becoming a disease-changing therapeutic option for these patients. In this review, we aim to summarise the development of this emerging field detailing the main gene therapy strategies, routes of administration, viral and non-viral vectors and gene editing tools. We discuss the respective advantages and pitfalls of these gene therapy strategies and review their application in IMD, providing examples of clinical trials with lentiviral or adeno-associated viral gene therapy vectors in rare diseases. The rapid development of the field and implementation of gene therapy as a realistic therapeutic option for various IMD in a short term also require a good knowledge and understanding of these technologies from physicians to counsel the patients at best.
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Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations.
Cremers, FPM, Lee, W, Collin, RWJ, Allikmets, R
Progress in retinal and eye research. 2020;:100861
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Abstract
The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.
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KCNV2 retinopathy: clinical features, molecular genetics and directions for future therapy.
Guimaraes, TAC, Georgiou, M, Robson, AG, Michaelides, M
Ophthalmic genetics. 2020;(3):208-215
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Abstract
-associated retinopathy or "cone dystrophy with supernormal rod responses" is an autosomal recessive cone-rod dystrophy with pathognomonic ERG findings. This gene encodes Kv8.2, a voltage-gated potassium channel subunit that acts as a modulator by shifting the activation range of the K+ channels in photoreceptor inner segments. Currently, no treatment is available for the condition. However, there is a lack of prospective long-term data in large molecularly confirmed cohorts, which is a prerequisite for accurate patient counselling/prognostication, to identify an optimal window for intervention and outcome measures, and ultimately to design future therapy trials. Herein we provide a detailed review of the clinical features, retinal imaging, electrophysiology and psychophysical studies, molecular genetics, and briefly discuss future prospects for therapy trials.
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The concept of disease modification.
Cross, JH, Lagae, L
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2020;:43-46
Abstract
Traditionally treatment of epileptic seizures has been symptomatic, namely medication has been targeted at raising the threshold to the occurrence of epileptic seizures. This has had little impact on the rate of drug resistance over time, or impact on comorbidities such as learning and behaviour particularly in the early onset epilepsies. The advent of advanced neuroimaging and genomics has revealed the cause of the epilepsy in a much higher percentage, and advanced our knowledge as to the underlying pathophysiology. This has given us the opportunity to turn to the possibility of interventional treatment, targeting the underlying cause, and consequently the possibility of changing the natural history of disease. Here we review the options open to us, and the evidence to date.
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Redifferentiation of radioiodine-refractory thyroid cancers.
Buffet, C, Wassermann, J, Hecht, F, Leenhardt, L, Dupuy, C, Groussin, L, Lussey-Lepoutre, C
Endocrine-related cancer. 2020;(5):R113-R132
Abstract
The management of radioiodine refractory thyroid cancers (RAIR TC) is challenging for the clinician. Tyrosine kinase inhibitors classically prescribed in this setting can fail due to primary or acquired resistance or the necessity of drug withdrawal because of serious or moderate but chronic and deleterious adverse effects. Thus, the concept of redifferentiation strategy, which involves treating patients with one or more drugs capable of restoring radioiodine sensitivity for RAIR TC, has emerged. The area of redifferentiation strategy leads to the creation of new definitions of RAIR TC including persistent non radioiodine-avid patients and 'true' RAIR TC patients. The latter group presents a restored or increased radioiodine uptake in metastatic lesions but with no radiological response on conventional imaging, that is, progression of a metastatic disease, thus proving that they are 'truly' resistant to the radiation delivered by radioiodine. Unlike these patients, metastatic TC patients with restored radioiodine uptake offer the hope of prolonged remission or even cure of the disease as for radioiodine-avid metastatic TC. Here, we review the different redifferentiation strategies based on the underlying molecular mechanism leading to the sodium iodide symporter (NIS) and radioiodine uptake reinduction, that is, by modulating signaling pathways, NIS transcription, NIS trafficking to the plasma membrane, NIS post-transcriptional regulation, by gene therapy and other potential strategies. We discuss clinical trials and promising preclinical data of potential future targets.
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Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation.
Motta, I, Bou-Fakhredin, R, Taher, AT, Cappellini, MD
Drugs. 2020;(11):1053-1063
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Abstract
Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation. The thalassemias are characterized by autosomal recessive inherited defects in the production of hemoglobin. They are highly prevalent in the Mediterranean, Middle East, Indian subcontinent, and East and Southeast Asia. Due to recent migrations, however, the thalassemias are now becoming more common in Europe and North America, making this disease a global health concern. Currently available conventional therapies in thalassemia have many challenges and limitations. A better understanding of the pathophysiology of β-thalassemia in addition to key developments in optimizing transfusion programs and iron-chelation therapy has led to an increase in the life span of thalassemia patients and paved the way for new therapeutic strategies. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. In this review, we provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.
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7.
Models of Technology Transfer for Genome-Editing Technologies.
Graff, GD, Sherkow, JS
Annual review of genomics and human genetics. 2020;:509-534
Abstract
Many of the fundamental inventions of genome editing, including meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR, were first made at universities and patented to encourage commercial development. This gave rise to a diversity of technology transfer models but also conflicts among them. Against a broader historical and policy backdrop of university patenting and special challenges concerning research tools, we review the patent estates of genome editing and the diversity of technology transfer models employed to commercialize them, including deposit in the public domain, open access contracts, material transfer agreements, nonexclusive and exclusive licenses, surrogate licenses, and aggregated licenses. Advantages are found in this diversity, allowing experimentation and competition that we characterize as a federalism model of technology transfer. A notable feature of genome editing has been the rise and success of third-party licensing intermediaries. At the same time, the rapid pace of development of genome-editing technology is likely to erode the importance of patent estates and licensing regimes and may mitigate the effect of overly broad patents, giving rise to new substitutes to effectuate commercialization.
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Recent developments in pediatric retina.
Cai, S, Therattil, A, Vajzovic, L
Current opinion in ophthalmology. 2020;(3):155-160
Abstract
PURPOSE OF REVIEW Pediatric retina is an exciting, but also challenging field, where patient age and cooperation can limit ease of diagnosis of a broad range of congenital and acquired diseases, inherited retinal degenerations are mostly untreatable and surgical outcomes can be quite different from those for adults. This review aims to highlight some recent advances and trends that are improving our ability to care for children with retinal conditions. RECENT FINDINGS Studies have demonstrated the feasibility of multimodal imaging even in nonsedated infants, with portable optical coherence tomography (OCT) and OCT angiography in particular offering structural insights into diverse pediatric retinal conditions. Encouraging long-term outcomes of subretinal voretigene neparvovec-rzyl injection for RPE65 mutation-associated Leber congenital amaurosis have inspired research on the optimization of subretinal gene delivery and gene therapy for other inherited retinal degenerations. In retinopathy of prematurity, machine learning and smartphone-based imaging can facilitate screening, and studies have highlighted favorable outcomes from intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. A nomogram for pediatric pars plana sclerotomy site placement may improve safety in complex surgeries. SUMMARY Multimodal imaging, gene therapy, machine learning and surgical innovation have been and will continue to be important to advances in pediatric retina.
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A new era of gene editing for the treatment of human diseases.
Kc, M, Steer, CJ
Swiss medical weekly. 2019;:w20021
Abstract
The treatment of human diseases using gene-editing technology has been envisioned for several decades with the realisation that so many were associated with mutations in DNA. The Human Genome Project opened new doors for identifying the genetic bases for human suffering. Research on gene editing has been active since the 1970s, but the technology has seen substantial growth and application just within the past decade. Simply stated, CRISPR technology has become a phenomenon in both biomedical and therapeutics research. Concurrently, cell therapies and pluripotent stem cell research have also been refined and now interfaced with CRISPR technology to enhance and maximise their potential in modelling as well as treatment of human diseases. In this review, we discuss the novel and revolutionary modality of gene editing, as this marks a new era in research and medicine. We also discuss gene-modifying technologies leading to CRISPR, as they are still being used for a wide variety of genomic applications. The modes and challenges for delivery of gene editing components are also discussed. Lastly, we review examples of human diseases that are not only amenable to gene editing techniques, but also show true promise of cure in the early 21st century of genetic correction and gene repair.
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Gene-function studies in systemic lupus erythematosus.
Rosetti, F, de la Cruz, A, Crispín, JC
Current opinion in rheumatology. 2019;(2):185-192
Abstract
PURPOSE OF REVIEW The aim of this review is to discuss recent developments in our understanding of how systemic lupus erythematosus (SLE)-associated genes contribute to autoimmunity. RECENT FINDINGS Gene-function studies have revealed mechanisms through which SLE-associated alleles of IFIH1, TNFAIP3, IRF5, and PRDM1 likely contribute to the development of autoimmunity. Novel research has identified Mac-1 (encoded by ITGAM), CaMK4, and iRhom2 as plausible therapeutic targets in lupus nephritis. SUMMARY The work discussed in this review has broad implications for our understanding of the pathogenesis of SLE and for the development of novel therapeutic strategies.