Literature Watch
Understanding aerobic/anaerobic metabolism in Caldibacillus debilis through a comparison with model organisms.
Understanding aerobic/anaerobic metabolism in Caldibacillus debilis through a comparison with model organisms.
Syst Appl Microbiol. 2017 Apr 13;:
Authors: Wushke S, Spicer V, Zhang XL, Fristensky B, Krokhin OV, Levin DB, Cicek N, Sparling R
Abstract
Caldibacillus debilis GB1 is a facultative anaerobe isolated from a thermophilic aero-tolerant cellulolytic enrichment culture. There is a lack of representative proteomes of facultative anaerobic thermophilic Bacillaceae, exploring aerobic/anaerobic expression. The C. debilis GB1 genome was sequenced and annotated, and the proteome characterized under aerobic and anaerobic conditions while grown on cellobiose. The draft sequence of C. debilis GB1 contains a 3,340,752 bp chromosome and a 5,386 bp plasmid distributed over 49 contigs. Two-dimensional liquid chromatography mass spectrometry/mass spectrometry was used with Isobaric Tags for Relative and Absolute Quantification (iTRAQ) to compare protein expression profiles, focusing on energy production and conversion pathways. Under aerobic conditions, proteins in glycolysis and pyruvate fermentation pathways were down-regulated. Simultaneously, proteins within the tricarboxylic acid cycle, pyruvate dehydrogenase, the electron transport chain, and oxygen scavenging pathways showed increased amounts. Under anaerobic conditions, protein levels in fermentation pathways were consistent with the generated end-products: formate, acetate, ethanol, lactate, and CO2. Under aerobic conditions CO2 and acetate production was consistent with incomplete respiration. Through a direct comparison with gene expression profiles from Escherichia coli, we show that global regulation of core metabolism pathways is similar in thermophilic and mesophilic facultative anaerobes of the Phylum Proteobacteria and Firmicutes.
PMID: 28527624 [PubMed - as supplied by publisher]
Developing Biomarkers for Trastuzumab-induced Cardiotoxicity (R30)
Notice of Intent to Publish a Funding Opportunity Announcement for NINR Exploratory Centers (P20)
Bioinformatics and in vitro experimental analyses identify the selective therapeutic potential of interferon gamma and apigenin against cervical squamous cell carcinoma and adenocarcinoma.
Bioinformatics and in vitro experimental analyses identify the selective therapeutic potential of interferon gamma and apigenin against cervical squamous cell carcinoma and adenocarcinoma.
Oncotarget. 2017 May 02;:
Authors: Yang PM, Chou CJ, Tseng SH, Hung CF
Abstract
The clinical management and treatment of cervical cancer, one of the most commonly diagnosed cancers and a leading cause of cancer-related female death, remains a huge challenge for researchers and health professionals. Cervical cancer can be categorized into two major subtypes: common squamous cell carcinoma (SCC) and adenocarcinoma (AC). Although it is a relatively rare histological subtype of cervical cancer, there has been a steady increase in the incidences of AC. Therefore, new strategies to treat cervical cancer are urgently needed. In this study, the potential uses of IFNγ-based therapy for cervical cancer were evaluated using bioinformatics approaches. Gene expression profiling identified that cell cycle dysregulation was a major hallmark of cervical cancer including SCC and AC subtypes, and was associated with poor clinical outcomes for cervical cancer patients. In silico and in vitro experimental analyses demonstrated that IFNγ treatment could reverse the cervical cancer hallmark and induce cell cycle arrest and apoptosis. Furthermore, we demonstrated that apigenin could enhance the anticancer activity of IFNγ in a HeLa cervical AC cell line by targeting cyclin-dependent kinase 1. Taken together, the present study suggests the selective therapeutic potential of IFNγ alone or in combination with apigenin for managing cervical SCC and AC.
PMID: 28526810 [PubMed - as supplied by publisher]
Hypothalamic regulation of the sleep/wake cycle.
Hypothalamic regulation of the sleep/wake cycle.
Neurosci Res. 2017 May 16;:
Authors: Ono D, Yamanaka A
Abstract
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial component for maintenance of wakefulness, because lack of orexin function results in narcolepsy, which is a sleep disorder. Recent findings have identified substances that excite or inhibit neural activity of orexin neurons. Furthermore neural projections of the neurons which release these substances have been revealed. In addition to orexin, melanin concentrating hormone (MCH)-producing neurons in the lateral hypothalamic area (LHA) are also implicated in the regulation of sleep/wakefulness. MCH neurons are active during sleep but become silent during wakefulness. Recently developed innovative methods including optogenetics and pharmacogenetics have provided substantial insights into the regulation of sleep/wakefulness. In vivo optical recordings and retrograde and anterograde tracing methods will allow us to understand additional details regarding important interactions between these two types of neurons in the LHA and other neurons in the brain. Finally we discuss the circadian clock and sleep/wakefulness cycle. Understanding of the neural networks and its circadian modulation of sleep/wakefulness cycles remain to be investigated.
PMID: 28526553 [PubMed - as supplied by publisher]
Pharmacogenomics in Pain Management.
Pharmacogenomics in Pain Management.
Anesthesiol Clin. 2017 Jun;35(2):295-304
Authors: Saba R, Kaye AD, Urman RD
Abstract
There is interpatient variability to analgesic administration. Much can be traced to pharmacogenomics variations between individuals. Certain ethnicities are more prone to reduced function of CYP2D6. Weak opioids are subject to interpatient variation based on their CYP2D6 type. Strong opioids have variations based on their transport and individual metabolism. Several cytochrome enzymes have been found to be involved with ketamine but there is no strong evidence of individual polymorphisms manifesting in clinical outcomes. Nonsteroidal anti-inflammatory drugs have adverse outcomes that certain CYP variants are more prone toward. There are now recommendations for dosing based on specific genomic makeup.
PMID: 28526150 [PubMed - in process]
Pharmacogenomics in Anesthesia.
Pharmacogenomics in Anesthesia.
Anesthesiol Clin. 2017 Jun;35(2):285-294
Authors: Saba R, Kaye AD, Urman RD
Abstract
A significant number of commonly administered medications in anesthesia show wide clinical interpatient variability. Some of these include neuromuscular blockers, opioids, local anesthetics, and inhalation anesthetics. Individual genetic makeup may account for and predict cardiovascular outcomes after cardiac surgery. These interactions can manifest at any point in the perioperative period and may also only affect a specific system. A better understanding of pharmacogenomics will allow for more individually tailored anesthetics and may ultimately lead to better outcomes, decreased hospital stays, and improved patient satisfaction.
PMID: 28526149 [PubMed - in process]
SurvivalGWAS_SV: software for the analysis of genome-wide association studies of imputed genotypes with "time-to-event" outcomes.
SurvivalGWAS_SV: software for the analysis of genome-wide association studies of imputed genotypes with "time-to-event" outcomes.
BMC Bioinformatics. 2017 May 19;18(1):265
Authors: Syed H, Jorgensen AL, Morris AP
Abstract
BACKGROUND: Analysis of genome-wide association studies (GWAS) with "time to event" outcomes have become increasingly popular, predominantly in the context of pharmacogenetics, where the survival endpoint could be death, disease remission or the occurrence of an adverse drug reaction. However, methodology and software that can efficiently handle the scale and complexity of genetic data from GWAS with time to event outcomes has not been extensively developed.
RESULTS: SurvivalGWAS_SV is an easy to use software implemented using C# and run on Linux, Mac OS X & Windows operating systems. SurvivalGWAS_SV is able to handle large scale genome-wide data, allowing for imputed genotypes by modelling time to event outcomes under a dosage model. Either a Cox proportional hazards or Weibull regression model is used for analysis. The software can adjust for multiple covariates and incorporate SNP-covariate interaction effects.
CONCLUSIONS: We introduce a new console application analysis tool for the analysis of GWAS with time to event outcomes. SurvivalGWAS_SV is compatible with high performance parallel computing clusters, thereby allowing efficient and effective analysis of large scale GWAS datasets, without incurring memory issues. With its particular relevance to pharmacogenetic GWAS, SurvivalGWAS_SV will aid in the identification of genetic biomarkers of patient response to treatment, with the ultimate goal of personalising therapeutic intervention for an array of diseases.
PMID: 28525968 [PubMed - in process]
Urging Europe to put non-adherence to inhaled respiratory medication higher on the policy agenda: a report from the First European Congress on Adherence to Therapy.
Urging Europe to put non-adherence to inhaled respiratory medication higher on the policy agenda: a report from the First European Congress on Adherence to Therapy.
Eur Respir J. 2017 May;49(5):
Authors: van Boven JFM, Lavorini F, Dekhuijzen PNR, Blasi F, Price DB, Viegi G
PMID: 28526801 [PubMed - in process]
Unfolding the pathogenesis of scleroderma through genomics and epigenomics.
Unfolding the pathogenesis of scleroderma through genomics and epigenomics.
J Autoimmun. 2017 May 16;:
Authors: Tsou PS, Sawalha AH
Abstract
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc.
PMID: 28526340 [PubMed - as supplied by publisher]
Next-generation sequencing for D47N mutation in Cx50 analysis associated with autosomal dominant congenital cataract in a six-generation Chinese family.
Next-generation sequencing for D47N mutation in Cx50 analysis associated with autosomal dominant congenital cataract in a six-generation Chinese family.
BMC Ophthalmol. 2017 May 19;17(1):73
Authors: Shen C, Wang J, Wu X, Wang F, Liu Y, Guo X, Zhang L, Cao Y, Cao X, Ma H
Abstract
BACKGROUND: Congenital cataract is the most frequent cause of blindness during infancy or early childhood. To date, more than 40 loci associated with congenital cataract have been identified, including at least 26 genes on different chromosomes associated with inherited cataract. This present study aimed to identify the genetic mutation in a six-generation Chinese family affected with congenital cataract.
METHODS: A detailed six-generation Chinese cataract family history and clinical data of the family members were recorded. A total of 27 family members, including 14 affected and 13 unaffected individuals were recruited. Whole exome sequencing was performed to determine the disease-causing mutation. Sanger sequencing was used to confirm the results.
RESULTS: A known missense mutation, c. 139G > A (p. D47N), in Cx50 was identified. This mutation co-segregated with all affected individuals and was not observed in the unaffected family members or in 100 unrelated controls. The homology modeling showed that the structure of the mutant protein was different with that wild-type Cx50.
CONCLUSIONS: The missense mutation c.139G > A in GJA8 gene is associated with autosomal dominant congenital cataract in a six-generation Chinese family. The result of this present study provides further evidence that the p. D47N mutation in CX50 is a hot-spot mutation.
PMID: 28526010 [PubMed - in process]
Making Time: Conservation of Biological Clocks from Fungi to Animals.
Making Time: Conservation of Biological Clocks from Fungi to Animals.
Microbiol Spectr. 2017 May;5(3):
Authors: Dunlap JC, Loros JJ
Abstract
The capacity for biological timekeeping arose at least three times through evolution, in prokaryotic cyanobacteria, in cells that evolved into higher plants, and within the group of organisms that eventually became the fungi and the animals. Neurospora is a tractable model system for understanding the molecular bases of circadian rhythms in the last of these groups, and is perhaps the most intensively studied circadian cell type. Rhythmic processes described in fungi include growth rate, stress responses, developmental capacity, and sporulation, as well as much of metabolism; fungi use clocks to anticipate daily environmental changes. A negative feedback loop comprises the core of the circadian system in fungi and animals. In Neurospora, the best studied fungal model, it is driven by two transcription factors, WC-1 and WC-2, that form the White Collar Complex (WCC). WCC elicits expression of the frq gene. FRQ complexes with other proteins, physically interacts with the WCC, and reduces its activity; the kinetics of these processes is strongly influenced by progressive phosphorylation of FRQ. When FRQ becomes sufficiently phosphorylated that it loses the ability to influence WCC activity, the circadian cycle starts again. Environmental cycles of light and temperature influence frq and FRQ expression and thereby reset the internal circadian clocks. The molecular basis of circadian output is also becoming understood. Taken together, molecular explanations are emerging for all the canonical circadian properties, providing a molecular and regulatory framework that may be extended to many members of the fungal and animal kingdoms, including humans.
PMID: 28527179 [PubMed - in process]
Gender Differences in the Association between Moderate Alcohol Consumption and Hearing Threshold Shifts.
Gender Differences in the Association between Moderate Alcohol Consumption and Hearing Threshold Shifts.
Sci Rep. 2017 May 19;7(1):2201
Authors: Lin YY, Chen HC, Lai WS, Wu LW, Wang CH, Lee JC, Kao TW, Chen WL
Abstract
Hearing loss is a global public health problem with a high prevalence, significantly impairing communication and leading to a decrease in the quality of life. The association between moderate alcohol consumption (MAC) and hearing impairment has been addressed in several studies with inconsistent results. The intent of our study is to clarify the correlation between MAC and the hearing threshold and further investigate the interplay between MAC and the hearing threshold categorized by gender. The study included 4,075 participants aged 20-69 years from the 1999-2004 data of National Health and Nutrition Examination Survey (NHANES). The associations among MAC, gender differences, and high-frequency and low-frequency hearing thresholds were analyzed. We found that current female drinkers with MAC tended to have lower hearing thresholds. There is a significant protective effect of MAC on hearing threshold shifts in the US adult population, especially in females. Our research was the first study to further indicate that there is a gender difference in the association between MAC and hearing impairment. In accordance with our results, if people drink, they should consume moderate rather than higher amounts, especially in women, which may result in a reduced risk of hearing loss.
PMID: 28526828 [PubMed - in process]
Cell fixation and preservation for droplet-based single-cell transcriptomics.
Cell fixation and preservation for droplet-based single-cell transcriptomics.
BMC Biol. 2017 May 19;15(1):44
Authors: Alles J, Karaiskos N, Praktiknjo SD, Grosswendt S, Wahle P, Ruffault PL, Ayoub S, Schreyer L, Boltengagen A, Birchmeier C, Zinzen R, Kocks C, Rajewsky N
Abstract
BACKGROUND: Recent developments in droplet-based microfluidics allow the transcriptional profiling of thousands of individual cells in a quantitative, highly parallel and cost-effective way. A critical, often limiting step is the preparation of cells in an unperturbed state, not altered by stress or ageing. Other challenges are rare cells that need to be collected over several days or samples prepared at different times or locations.
METHODS: Here, we used chemical fixation to address these problems. Methanol fixation allowed us to stabilise and preserve dissociated cells for weeks without compromising single-cell RNA sequencing data.
RESULTS: By using mixtures of fixed, cultured human and mouse cells, we first showed that individual transcriptomes could be confidently assigned to one of the two species. Single-cell gene expression from live and fixed samples correlated well with bulk mRNA-seq data. We then applied methanol fixation to transcriptionally profile primary cells from dissociated, complex tissues. Low RNA content cells from Drosophila embryos, as well as mouse hindbrain and cerebellum cells prepared by fluorescence-activated cell sorting, were successfully analysed after fixation, storage and single-cell droplet RNA-seq. We were able to identify diverse cell populations, including neuronal subtypes. As an additional resource, we provide 'dropbead', an R package for exploratory data analysis, visualization and filtering of Drop-seq data.
CONCLUSIONS: We expect that the availability of a simple cell fixation method will open up many new opportunities in diverse biological contexts to analyse transcriptional dynamics at single-cell resolution.
PMID: 28526029 [PubMed - in process]
[Adverse drug reactions in neonates hospitalized in neonatal intensive care units in Barranquilla, Colombia].
[Adverse drug reactions in neonates hospitalized in neonatal intensive care units in Barranquilla, Colombia].
Biomedica. 2017 Apr 01;37(0):33-42
Authors: De Las Salas R, Díaz-Agudelo D
Abstract
INTRODUCTION: The appearance of adverse drug reactions in neonates is an important issue due to the lack of drug safety data.
OBJECTIVE: To identify the behavior of adverse drug reactions (ADR) in hospitalized neonates at two intensive care units in Barranquilla, Colombia.
MATERIALS AND METHODS: We conducted a cross-sectional prospective descriptive study based on patientcentered intensive pharmacosurveillance. We followed up and monitored the appearance of ADRs for six months. We used Naranjo's algorithm to assess causality, modified Hartwig and Siegel assessment scale to establish severity and Schumock and Thornton criteria to determine ADR preventability.
RESULTS: We detected 123 adverse drug reactions in 78 neonates of the 284 monitored. The cumulative incidence of ADRs was 27.4% (78/284); incidence density was 30.60 ADRs per 1,000 patients/day (78/2,549). The most affected organ system was the digestive (33.6%). Systemic anti-infective drugs were the most involved pharmacological group. Most of the ADRs were mild (58.5%), 83% were classified as probable, 16.2% as possible and 0.8% as definite.
CONCLUSIONS: ADR incidence was high in newborns, and it increased in preterm infants (less than 38 weeks of age).
PMID: 28527264 [PubMed - in process]
Characterisation of Drug-Related Problems and Associated Factors at a Clinical Pharmacist Service-Naïve Hospital in Northern Sweden.
Characterisation of Drug-Related Problems and Associated Factors at a Clinical Pharmacist Service-Naïve Hospital in Northern Sweden.
Drugs Real World Outcomes. 2017 May 19;:
Authors: Peterson C, Gustafsson M
Abstract
BACKGROUND: Polypharmacy and increased sensitivity to side effects cause adverse drug events, drug-drug interactions and medication errors in the elderly.
OBJECTIVE: The objective of this study was to investigate the prevalence and type of drug-related problems and associated factors among patients admitted to a clinical pharmacist service-naïve medical ward in an inland hospital in northern Sweden.
METHODS: During September-November 2015 and February-April 2016, clinical pharmacists working as part of a ward team on the medical ward conducted 103 medication reviews. Drug-related problems were identified and classified. Associated factors, drug classes and specific drugs involved were also investigated.
RESULTS: The clinical pharmacists identified 133 drug-related problems in 66% [68/103] of the study population. The most common drug-related problems in this study were inappropriate drug use and interactions. Cardiovascular drugs and psychotropic drugs were most commonly involved. Drug-related problems were more frequently observed at higher age, increasing number of drugs prescribed and in patients with reduced renal function. In the multivariate analysis, only the number of prescribed drugs was still significant.
CONCLUSION: Drug-related problems were commonly observed among patients admitted to the medical ward. Medication reviews conducted by clinical pharmacists as part of a ward team resulted in several interventions to improve the patients' drug treatment.
PMID: 28527149 [PubMed - as supplied by publisher]
A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C.
A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C.
Invest New Drugs. 2017 May 19;:
Authors: Almhanna K, Wright D, Mercade TM, Van Laethem JL, Gracian AC, Guillen-Ponce C, Faris J, Lopez CM, Hubner RA, Bendell J, Bols A, Feliu J, Starling N, Enzinger P, Mahalingham D, Messersmith W, Yang H, Fasanmade A, Danaee H, Kalebic T
Abstract
Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.
PMID: 28527133 [PubMed - as supplied by publisher]
Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma.
Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma.
Oncologist. 2017 May 18;:
Authors: Daud A, Tsai K
Abstract
Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients. Because the goal of treatment is to prolong survival with minimal impairment of quality of life, drug-related adverse events (AEs) require prompt management to ensure that patients derive the best possible benefit from therapy. Proper management depends on an understanding of which AEs are most likely BRAF or MEK inhibitor associated, thus providing a rationale for dose modification of the appropriate drug. Additionally, the unique safety profile of the chosen regimen may influence patient selection and monitoring. This review discusses the toxicity profiles of these agents, with a focus on the most commonly reported and serious AEs. Here, we offer practical guidance derived from our clinical experience for the optimal management of key drug-related AEs. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage BRAF V600-mutant metastatic melanoma. To provide optimal therapeutic benefit to patients, clinicians need a keen understanding of the toxicity profiles of these drugs. Prompt identification and an understanding of which adverse events are most likely BRAF or MEK inhibitor associated provide a rationale for appropriate therapy adjustments. Practical recommendations derived from clinical experience are provided for management of key drug-related toxicities.
PMID: 28526719 [PubMed - as supplied by publisher]
Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.
Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial.
Lancet. 2017 May 16;:
Authors: Heier JS, Kherani S, Desai S, Dugel P, Kaushal S, Cheng SH, Delacono C, Purvis A, Richards S, Le-Halpere A, Connelly J, Wadsworth SC, Varona R, Buggage R, Scaria A, Campochiaro PA
Abstract
BACKGROUND: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration.
METHODS: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2 × 10(8) vector genomes (vg); cohort 2, 2 × 10(9) vg; cohort 3, 6 × 10(9) vg; and cohort 4, 2 × 10(10) vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2 × 10(10) vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998.
FINDINGS: 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 × 10(10) vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2 × 10(10) vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were negative for anti-AAV2 serum antibodies and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related.
INTERPRETATION: Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies.
FUNDING: Sanofi Genzyme, Framingham, MA, USA.
PMID: 28526489 [PubMed - as supplied by publisher]
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