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Preclinical development of a dual targeting bicistronic gene therapy approach for the treatment of wet age-related macular degeneration
No full textAge-related macular degeneration (AMD) continues to be a leading cause of severe vision impairment affecting millions worldwide. The late stages of AMD are characterized by outer retinal atrophy (geographic atrophy, GA), or neovascularization associated with subretinal and/or intraretinal exudation (exudative neovascular or ‘wet’ AMD). Intravitreal (IVT) administration of anti-vascular endothelial growth factor (VEGF) therapies has dramatically improved vision preservation for wet AMD (wAMD) patients. However, current Standard of Care (SoC) has significant shortcomings and the benefits of anti-VEGF therapy in the real-world setting fall short of the vision gains observed in randomized clinical trials. This is thought to be attributable to drug burden to patients, lack of therapeutic durability due to progression of underlying macular atrophy and refractility to treatment. Vectorized anti-VEGF therapy has been shown to be effective in reducing drug burden clinically but is unlikely to address the progression of the underlying GA driven by complement-mediated inflammation. Here, we aim to address this unmet need by developing a bicistronic gene therapy vector co-expressing aflibercept and Factor H-like protein 1 (FHL-1) to target the pro-angiogenic and pro-inflammatory environment of wAMD. In vitro assays confirmed the anti-angiogenic and complement inhibitory properties of the bicistronic vector. Recombinant AAV8 (rAAV8)-mediated co-expression was detected for up to 4 weeks following subretinal delivery in wild type (WT) mice. In a mouse laser-induced choroidal neovascularization (CNV) model, subretinal delivery of bicistronic vectors significantly reduced both CNV leakage and lesion. These results demonstrate that a single subretinal administration of bicistronic vector may provide an effective treatment option for wAMD and may also prolong patient’s visual outcomes by preventing the underlying progression of GA
A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution.
No full textOnly a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters
People of TM: Video of Aleksandra Seydel
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content
Points to consider regarding the use and implementation of virtual controls in nonclinical toxicology studies
No full textNo abstrac
Pharmacokinetics of ganaplacide and lumefantrine: data from a Phase 2 study in adults, adolescents, and children with Plasmodium falciparum malaria in Africa treated with ganaplacide plus lumefantrine solid dispersion formulation
No full textThe novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well-tolerated in the treatment of falciparum malaria in adults, adolescents and children in a randomized, active-controlled Phase 2 trial (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here.
The trial comprised a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential PK interactions between ganaplacide and lumefantrine; in Part A, 337 adult/adolescent patients received one of six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in 175 children aged 2 to <12 years old, body weight ≥10 kg. A rich blood sampling schedule was used for all patients in the PK run-in part and a subset of patients in Part A, with sparse sampling for remaining patients in Parts A and B.
Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0-t, Cmax and tmax were reported where possible, using non-compartmental analysis.
In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure on co-administration. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24h) were comparable across age and body weight groups
Condensation domain editing of the FR900359 assembly line yield a novel analog amenable to late-stage functionalization
No full textThe natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein-coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure-activity-relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid-phase peptide synthesis. Options for late-stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR-assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold
A call for an industry-led initiative to critically assess machine learning for real-world drug discovery
No full textno abstrac
Anchor-based minimal important difference values are often sensitive to the distribution of the change score.
No full textAnchor-based studies are today the most popular approach to determine a minimal important difference value for an outcome variable. However, a variety of construction methods for such values do exist. This constitutes a challenge to the field. In order to distinguish between more or less adequate construction methods, meaningful minimal requirements can be helpful. For example, minimal important difference values should not reflect the intervention(s) the patients are exposed to in the study used for construction, as they should later allow to compare interventions. This requires that they are not sensitive to the distribution of the change score observed. This study aims at investigating to which degree established construction methods fulfil this minimal requirement.Six constructions methods were considered, covering very popular and recently suggested methods. The sensitivity of MID values to the distribution of the change score was investigated in a simulation study for these six construction methods.Five out of six construction methods turned out to yield MID values which are sensitive to the distribution of the change score to a degree that questions their usefulness. Insensitivity can be obtained by using construction methods based solely on an estimate of the conditional distribution of the anchor variable given the change score.In future the computation of MID values should be based on construction methods avoiding sensitivity to the distribution of the change score
Prognostic value of B-score for predicting joint replacement in the context of osteoarthritis phenotypes: Data from the osteoarthritis initiative
No full textObjective
Developing new therapies for knee osteoarthritis (KOA) requires improved prediction of disease progression. This study evaluated the prognostic value of clinical clusters and machine-learning derived quantitative 3D bone shape B-score for predicting total and partial knee replacement (KR).
Design
This retrospective study used longitudinal data from the Osteoarthritis Initiative. A previous study used patients' clinical profiles to delineate phenotypic clusters. For these clusters, the distribution of B-scores was assessed (employing Tukey's method). The value of both cluster allocation and B-score for KR-prediction was then evaluated using multivariable Cox regression models and Kaplan-Meier curves for time-to-event analyses. The impact of using B-score vs. cluster was evaluated using a likelihood ratio test for the multivariable Cox model; global performances were assessed by concordance statistics (Harrell's C-index) and time dependent receiver operating characteristic (ROC) curves.
Results
B-score differed significantly for the individual clinical clusters (p < 0.001). Overall, 9.4% of participants had a KR over 9 years, with a shorter time to event in clusters with high B-score at baseline. Those clusters were characterized clinically by a high rate of comorbidities and potential signs of inflammation. Both phenotype and B-score independently predicted KR, with better prediction if combined (P < 0.001). B-score added predictive value in groups with less pain and radiographic severity but limited physical activity.
Conclusions
B-scores correlated with phenotypes based on clinical patient profiles. B-score and phenotype independently predicted KR surgery, with higher predictive value if combined. This can be used for patient stratification in drug development and potentially risk prediction in clinical practice
Selective and Greener Methodologies in Organic Chemistry: A Pathway Towards Sustainable Future
No full textOver the centuries, industrial growth has been considered significant to modern civilization. However, along with its positive impacts, industrial development adversely affected the environment ranging from soil degradation, deforestation, ozone depletion, climate change, and water- and air pollution, leading to the loss of biodiversity.1–3 As we progress through the 21st century, we face enormous challenges, such as global warming by consistent increase in CO2 levels, causing melting of glaciers, resulting in a rise in ocean level at the rate of 3.42 mm per year.4,5 In addition, climate change with water and air pollution affects the quality of human lives.6,7 The human impact on the environment cannot be reversed. However, there is a need for ‘‘Sustainable Development’’ by using natural resources more sustainably than used in the past. To address these challenges, Green Chemistry is revolutionizing chemical processes and technologies towards a sustainable future by incorporating non-toxic and greener reactants and solvents, minimizing or eliminating toxic transition-metal catalysts, boosting reaction’s efficiency with greener additives, and providing environmentally benign synthetic routes with high atom-economy.8–1