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Expert Opinion on Orphan Drugs

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https://www.readbyqxmd.com/read/27547594/genetics-and-prospective-therapeutic-targets-for-sj%C3%A3-gren-larsson-syndrome
#1
William B Rizzo
INTRODUCTION: Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression...
April 2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27867771/prospect-and-progress-of-oncolytic-viruses-for-treating-peripheral-nerve-sheath-tumors
#2
Slawomir Antoszczyk, Samuel D Rabkin
INTRODUCTION: Peripheral nerve sheath tumors (PNSTs) are an assorted group of neoplasms originating from neuroectoderm and growing in peripheral nerves. Malignant transformation leads to a poor prognosis and is often lethal. Current treatment of PNSTs is predominantly surgical, which is often incomplete or accompanied by significant loss of function, in conjunction with radiotherapy and/or chemotherapy, for which the benefits are inconclusive. Oncolytic viruses (OVs) efficiently kill tumor cells while remaining safe for normal tissues, and are a novel antitumor therapy for patients with PNSTs...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27833825/epidemiology-pathogenesis-and-diagnosis-of-lymphangioleiomyomatosis
#3
Angelo M Taveira-DaSilva, Joel Moss
INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a disease of women characterized by cystic lung destruction, lymphatic involvement, and renal angiomyolipomas. AREAS COVERED: LAM is caused by proliferation of abnormal smooth muscle-like LAM cells containing mutations and perhaps epigenetic modifications of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins controlling the mechanistic target of rapamycin (mTOR) signaling pathway...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27812432/treatment-of-rapidly-progressive-systemic-sclerosis-current-and-futures-perspectives
#4
Fabian A Mendoza, Maryah Mansoor, Sergio A Jimenez
INTRODUCTION: Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality. AREAS COVERED: This paper reviews currently available therapeutic approaches for rapidly progressive SSc and discuss novel drugs under study for SSc disease modification...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27597930/pembrolizumab-for-the-treatment-of-advanced-melanoma
#5
Michael C Burns, Aidan O'Donnell, Igor Puzanov
INTRODUCTION: Since 2010 multiple targeted therapies and immunotherapies have been approved for the treatment of advanced melanoma. Pembrolizumab, a humanized monoclonal antibody directed against programed death receptor 1 has shown significant activity in advanced melanoma resulting in its approval first as post-ipilimumab and subsequently as frontline treatment. AREAS COVERED: This article reviews the approved agents for the treatment of advanced melanoma with a focus on the preclinical and clinical evidence for the use of pembrolizumab in this setting...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27340611/prospect-of-gene-therapy-for-cardiomyopathy-in-hereditary-muscular-dystrophy
#6
Yongping Yue, Ibrahim M Binalsheikh, Stacey B Leach, Timothy L Domeier, Dongsheng Duan
INTRODUCTION: Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies...
2016: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26973801/enzyme-replacement-therapy-for-treating-mucopolysaccharidosis-type-iva-morquio-a-syndrome-effect-and-limitations
#7
Shunji Tomatsu, Kazuki Sawamoto, Tsutomu Shimada, Michael B Bober, Francyne Kubaski, Eriko Yasuda, Robert W Mason, Shaukat Khan, Carlos J Alméciga-Díaz, Luis A Barrera, William G Mackenzie, Tadao Orii
INTRODUCTION: Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. AREAS COVERED: Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2...
November 1, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26635999/new-therapeutic-targets-in-rare-genetic-skeletal-diseases
#8
Michael D Briggs, Peter A Bell, Michael J Wright, Katarzyna A Pirog
Introduction: Genetic skeletal diseases (GSDs) are a diverse and complex group of rare genetic conditions that affect the development and homeostasis of the skeleton. Although individually rare, as a group of related diseases, GSDs have an overall prevalence of at least 1 per 4,000 children. There are currently very few specific therapeutic interventions to prevent, halt or modify skeletal disease progression and therefore the generation of new and effective treatments requires novel and innovative research that can identify tractable therapeutic targets and biomarkers of these diseases...
October 3, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26251765/pathogenic-mechanisms-and-the-prospect-of-gene-therapy-for-choroideremia
#9
Ioannis S Dimopoulos, Stephanie Chan, Robert E MacLaren, Ian M MacDonald
INTRODUCTION: Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss. AREAS COVERED: This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering the retinopathy to preclinical testing of potential therapies...
July 1, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26246977/improvement-in-vision-a-new-goal-for-treatment-of-hereditary-retinal-degenerations
#10
Samuel G Jacobson, Artur V Cideciyan, Gustavo D Aguirre, Alejandro J Roman, Alexander Sumaroka, William W Hauswirth, Krzysztof Palczewski
Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances...
May 4, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/25995973/the-road-to-cure-in-multiple-myeloma-starts-with-smoldering-disease
#11
Karma Z Salem, Irene M Ghobrial
INTRODUCTION: Smoldering multiple myeloma (SMM) is a heterogeneous clinical entity that defines patients in the spectrum of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Current standard of care is observation until end organ damage occurs. In spite of this, the scientific community has begun to question whether the strategy of watchful waiting should be replaced with earlier therapeutic intervention with the ultimate goal of preventing clonal heterogeneity and end organ damage...
April 12, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26998415/genetics-diagnosis-and-future-treatment-strategies-for-primary-ciliary-dyskinesia
#12
M Leigh Anne Daniels, Peadar G Noone
INTRODUCTION: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder resulting in chronic oto-sino-pulmonary disease. While PCD is estimated to occur in 1 in 20,000 individuals, fewer than 1,000 patients in the US have a well-established diagnosis. AREAS COVERED: We provide an overview of the clinical manifestations of PCD, describe the evolution of diagnostic methods, and critique the literature on management of PCD. EXPERT OPINION: Although interest in clinical studies in non-CF bronchiectasis has increased in recent years, some of whom enroll patients with PCD, the literature regarding therapy for PCD as a distinct entity is lacking, as the numbers are small, and there have been no sub-analyses published...
March 1, 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/25734025/pathogenesis-epidemiology-diagnosis-and-clinical-aspects-of-smith-lemli-opitz-syndrome
#13
Simona E Bianconi, Joanna L Cross, Christopher A Wassif, Forbes D Porter
INTRODUCTION: Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability. AREAS COVERED: In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients...
March 2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27668135/recombinant-adeno-associated-virus-vectors-in-the-treatment-of-rare-diseases
#14
Eric Hastie, R Jude Samulski
INTRODUCTION: An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27570714/ramucirumab-for-the-treatment-of-gastroesophageal-cancers
#15
Y Shimodaira, E Elimova, R Wadhwa, H Shiozaki, N Charalampakis, V Planjery, J E Rogers, S Song, J A Ajani
INTRODUCTION: In 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in the second line setting of advanced or metastatic, gastric or gastroesophageal adenocarcinoma (GEAC) based on the result of Phase III clinical trials; REGARD and RAINBOW. AREAS COVERED: We briefly review the mechanisms of angiogenesis, anti-angiogenic therapy, and current status of advanced GEAC treatment then highlight the challenges and future prospects of novel molecular targeted agents...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27559494/novel-therapeutic-strategies-for-the-management-of-ventricular-arrhythmias-associated-with-the-brugada-syndrome
#16
Bence Patocskai, Charles Antzelevitch
INTRODUCTION: Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome characterized by prominent J waves appearing as distinct coved type ST segment elevation in the right precordial leads of the ECG. It is associated with a high risk for sudden cardiac death. AREAS COVERED: We discuss 1) ECG manifestations of BrS which can be unmasked or aggravated by sodium channel blockers, febrile states, vagotonic agents, as well as tricyclic and tetracyclic antidepressants; 2) Genetic basis of BrS; 3) Ionic and cellular mechanisms underlying BrS; 4) Therapy involving devices including an implantable cardioverter defibrillator (ICD); 5) Therapy involving radiofrequency ablation; and 6) Therapy involving pharmacological therapy which is aimed at producing an inward shift in the balance of the currents active during phase 1 of the right ventricular action potential either by boosting calcium channel current (isoproterenol, cilostazol and milrinone) or by inhibition of transient outward current Ito (quinidine, bepridil and the Chinese herb extract Wenxin Keli)...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27547593/diagnosis-prevalence-and-screening-of-familial-dilated-cardiomyopathy
#17
Mary Sweet, Matthew R G Taylor, Luisa Mestroni
INTRODUCTION: Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and occurs often in families. As an inherited disease, understanding the significance of diagnostic procedures and genetic screening within families is of utmost importance. AREAS COVERED: Genetic studies have shown that in 30-40% of familial DCM (FDC) cases a causative genetic mutation can be identified. Successful genetic analysis is highly dependent on close examination of patient and family history, and clinical guidelines exist recommending genetic testing to aid in the evaluation of family members at risk of developing FDC...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/27525197/evaluating-a-novel-treatment-for-coronary-artery-inflammation-in-acute-kawasaki-disease-a-phase-i-iia-trial-of-atorvastatin
#18
Adriana H Tremoulet, Sonia Jain, Jane C Burns
INTRODUCTION: Since the 1980s, the primary treatment of acute Kawasaki disease (KD) has been intravenous immunoglobulin and aspirin. However, 5-10% of children with acute KD will develop coronary artery abnormalities despite treatment within the first ten days after fever onset. There is no approved adjunctive therapy to prevent progression of coronary artery damage in these patients. AREAS COVERED: The rationale and study design of a Phase I/IIa trial of atorvastatin in children with acute KD and coronary artery inflammation is presented...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26949572/pathogenesis-emerging-therapeutic-targets-and-treatment-in-sialidosis
#19
Alessandra d'Azzo, Eda Machado, Ida Annunziata
INTRODUCTION: Sialidosis is a neurosomatic, lysosomal storage disease (LSD) caused by mutations in the NEU1 gene, encoding the lysosomal sialidase NEU1. Deficient enzyme activity results in impaired processing/degradation of sialo-glycoproteins, and accumulation of oversialylated metabolites. Sialidosis is considered an orphan disorder for which no therapy is currently available. AREAS COVERED: The review describes the clinical forms of sialidosis and the NEU1 mutations so far identified; NEU1 requirement to complex with the protective protein/cathepsin A for stability and activation; and the pathogenic effects of NEU1 deficiency...
2015: Expert Opinion on Orphan Drugs
https://www.readbyqxmd.com/read/26900534/obstacles-and-future-of-gene-therapy-for-hemophilia
#20
Valder R Arruda, Ben J Samelson-Jones
INTRODUCTION: The recent success of early-phase clinical trials for adeno-associated viral (AAV) liver-directed gene therapy for hemophilia B (HB) demonstrates the potential for gene therapy, in the future, to succeed protein-based prophylaxis therapy for HB. Significant obstacles, however, need to be overcome prior to widespread adoption. The largest obstacles include immune responses to the AAV capsid including preexisting neutralizing antibodies (NAbs) and a delayed cellular immune response...
2015: Expert Opinion on Orphan Drugs
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