The progress of AAV-mediated gene therapy in neuromuscular disorders

INTRODUCTION: The well-defined genetic causes and monogenetic nature of many neuromuscular disorders, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), present gene therapy as a prominent therapeutic approach. The novel variants of adeno-associated virus (AAV) can achieve satisfactory transduction efficiency of exogenous genes through the central nervous system and body-wide in skeletal muscle. AREAS COVERED: In this review, we summarize the strategies of AAV gene therapy that are currently under preclinical and clinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on diseases such as DMD and SMA. In addition to gene replacement strategy, we provide an overview of other approaches such as AAV-mediated RNA therapy and gene editing in the treatment of muscular dystrophies. EXPERT OPINION: AAV gene therapy has achieved striking therapeutic efficacy in clinical trials in infants with SMA. Promising results have also come from the preclinical studies in small and large animal models of DMD and several clinical trials are now on the way. This strategy shows great potential as a therapy for various neuromuscular disorders. Further studies are still required to confirm its long-term safety and improve the efficacy

Computational drug discovery under RNA times

RNA molecules play many functional and regulatory roles in cells, and hence, have gained considerable traction in recent times as therapeutic interventions. Within drug discovery, structure-based approaches have successfully identified potent and selective small-molecule modulators of pharmaceutically relevant protein targets. Here, we embrace the perspective of computational chemists who use these traditional approaches, and we discuss the challenges of extending these methods to target RNA molecules. In particular, we focus on recognition between RNA and small-molecule binders, on selectivity, and on the expected properties of RNA ligands

Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are the second most common form of congenital muscular dystrophy. Currently, there is no effective treatment available. COL6-CMDs are caused by recessive or dominant mutations in one of the three genes encoding for the α chains of collagen type VI (COL6A1, COL6A2, and COL6A3). One of the most common mutations in COL6-CMD patients is a de novo deep intronic c.930+189C > T mutation in COL6A1 gene. This mutation creates a cryptic donor splice site and induces incorporation of a novel in-frame pseudo-exon in the mature transcripts. In this study, we systematically evaluated the splice switching approach using antisense oligonucleotides (ASOs) to correct this mutation. Fifteen ASOs were designed using the RNA-tiling approach to target the misspliced pseudo-exon and its flanking sequences. The efficiency of ASOs was evaluated at RNA, protein, and structural levels in skin fibroblasts established from four patients carrying the c.930+189C > T mutation. We identified two additional lead ASO candidates that efficiently induce pseudo-exon exclusion from the mature transcripts, thus allowing for the restoration of a functional collagen VI microfibrillar matrix. Our findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common intronic mutation

Early phase of massive star formation: A case study of Infrared dark cloud G084.81-01.09

We mapped the MSX dark cloud G084.81-01.09 in the NH3 (1,1) - (4,4) lines and in the J = 1-0 transitions of 12CO, 13CO, C18O and HCO+ in order to study the physical properties of infrared dark clouds, and to better understand the initial conditions for massive star formation. Six ammonia cores are identified with masses ranging from 60 to 250 M_sun, a kinetic temperature of 12 K, and a molecular hydrogen number density n(H2) ~ 10^5 cm^-3. In our high mass cores, the ammonia line width of 1 km/s is larger than those found in lower mass cores but narrower than the more evolved massive ones. We detected self-reversed profiles in HCO+ across the northern part of our cloud and velocity gradients in different molecules. These indicate an expanding motion in the outer layer and more complex motions of the clumps more inside our cloud. We also discuss the millimeter wave continuum from the dust. These properties indicate that our cloud is a potential site of massive star formation but is still in a very early evolutionary stage

Il sacro. A cento anni dalla pubblicazione di Das Heilige di Rudolf Otto

A cento anni dalla pubblicazione dell'opera principale di Rudolf Otto, Das Heilige, diversi specialisti si interrogano sulla sua rilevanza teorica nel panorama filosofico-religioso contemporaneo

Interweaving activities, feedback and learner model in a learner centered learning environment

International trends in education show a shift to student-centered approaches. This paper presents the Learner centered Learning (LcL) environment which is activity oriented, serves learning and assessment, provides multiple types of informative and tutoring feedback components at activity and question level and deploys open learner model to promote self-regulation. The use of the environment in higher education reveals positive results in learning and a promising blending of activities, feedback and open learner model. © Springer Nature Switzerland AG 2020

A Novel In Situ Hybridisation (Ish) Assay Mapping The In-Frame Pseudoexon 11 (Pe11) Expression In Cultured Dermal Fibroblasts (Cdf) And Skeletal Muscle In Patients With Severe Collagen Vi Disease Due To A Deep Intronic Mutation In Col6A1

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Distance Learning Library Services in Ugandan Universities

The study carried out at Makerere University and Uganda Martyrs University in 2010 aimed at providing strategies for enhanced distance learning library services in terms of convenience and adequacy. The study adopted a cross sectional descriptive survey design. The study revealed services provided in branch libraries in Ugandan universities were inadequate compared to the main libraries in the main campuses. The library services were convenient to a few of distance learners. About 209 (61.8%) learners from the two universities studied could not easily access the library services provided in the universities and 18 (5.3%) did not access them at all