Pilot-scale production of inactivated monoglycosylated split HN influenza virus vaccine provides cross-strain protection against influenza viruses.

Influenza epidemics and pandemics caused by newly emerging virus strains highlight an urgent need to develop a universal vaccine against viruses. Previously, a monoglycosylated X-181 vaccine demonstrated that the HA possessing a single N-acetylglucosamine at each N-glycosylation site is superior to confer broader protection in mice than conventional vaccines. However, the greatest challenge in conducting clinical trials is the need to develop robust manufacturing processes capable of producing vaccines at the pilot scale with the desired stability, potency, and efficacy.

Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach.

The development of drug delivery strategies for efficacious therapeutic administration directly into the central nervous system (CNS) in a minimally invasive manner remains a major obstacle hindering the clinical translation of biological disease-modifying therapeutics. A novel direct trans-nasal delivery method, termed 'Minimally-Invasive Nasal Depot' (MIND), has proved to be successful in providing high CNS uptake and brain distribution of blood-brain barrier (BBB) impermeant therapeutics via direct administration to the olfactory submucosal space in a rodent model. The present study describes the engineering of custom-made implants with a unique architecture of an "osmotically-active core" entrapping the therapeutic and a "biodegradable polymeric shell" to enable long-acting delivery using the MIND procedure.

Nucleic Acid-Based Therapeutics in Orphan Neurological Disorders: Recent Developments.

The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid-based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood-brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support.

Endonasal CNS Delivery System for Blood-Brain Barrier Impermeant Therapeutic Oligonucleotides Using Heterotopic Mucosal Engrafting.

The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB), which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson's disease (PD) as it can reverse disease progression. BDNF AntagoNAT's (ATs) are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression.

Minimally Invasive Nasal Depot (MIND) technique for direct BDNF AntagoNAT delivery to the brain.

The limitations of central nervous system (CNS) drug delivery conferred by the blood-brain barrier (BBB) have been a significant obstacle in the development of large molecule therapeutics for CNS disease. Though significantly safer than direct CNS administration via intrathecal (IT) or intracerebroventricular (ICV) injection, the topical intranasal delivery of CNS therapeutics has failed to become clinically useful due to a variety of practical and physiologic drawbacks leading to high dose variability and poor bioavailability. This study describes the minimally invasive nasal depot (MIND) technique, a novel method of direct trans-nasal CNS drug delivery which overcomes the dosing variability and efficiency challenges of traditional topical trans-nasal, trans-olfactory strategies by delivering the entire therapeutic dose directly to the olfactory submucosal space.

Developments in lncRNA drug discovery: where are we heading?

The central dogma of molecular biology, which states that the only role of long RNA transcripts is to convey information from gene to protein, was brought into question in recent years due to discovery of the extensive presence and complex roles of long noncoding RNAs (lncRNAs). Furthermore, lncRNAs were found to be involved in pathogenesis of multiple diseases and thus represent a new class of therapeutic targets. Translational efforts in the lncRNA field have been augmented by progress in optimizing the chemistry and delivery platforms of lncRNA-targeting modalities, including oligonucleotide-based drugs and CRISPR-Cas9.

Characterization and Pharmacokinetics of Triamcinolone Acetonide-Loaded Liposomes Topical Formulations for Vitreoretinal Drug Delivery.

Purpose: To achieve a safer alternative to intravitreal injection of corticosteroids, we developed and characterized triamcinolone acetonide-loaded liposomes formulations (TA-LFs) to be used topically for vitreoretinal drug delivery.

Methods: Four different 0.2% TA-LFs (TA-LF1 to TA-LF4) were generated and submitted to physicochemical characterization.

Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development.

Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1.

Natural antisense transcripts.

Recent years have seen the increasing understanding of the crucial role of RNA in the functioning of the eukaryotic genome. These discoveries, fueled by the achievements of the FANTOM, and later GENCODE and ENCODE consortia, led to the recognition of the important regulatory roles of natural antisense transcripts (NATs) arising from what was previously thought to be 'junk DNA'. Roughly defined as non-coding regulatory RNA transcribed from the opposite strand of a coding gene locus, NATs are proving to be a heterogeneous group with high potential for therapeutic application.

Regulation of the apolipoprotein gene cluster by a long noncoding RNA.

Apolipoprotein A1 (APOA1) is the major protein component of high-density lipoprotein (HDL) in plasma. We have identified an endogenously expressed long noncoding natural antisense transcript, APOA1-AS, which acts as a negative transcriptional regulator of APOA1 both in vitro and in vivo. Inhibition of APOA1-AS in cultured cells resulted in the increased expression of APOA1 and two neighboring genes in the APO cluster.

Oligonucleotides for upregulating gene expression.

Over the recent decade oligonucleotides have become an important new class of molecules, allowing therapeutic intervention through targets previously thought 'undruggable'. One of the new avenues opened up by oligonucleotide-based drugs was specific gene upregulation, which, historically, has been difficult to achieve using small-molecule drugs. This article will focus on patents covering this important development in the oligonucleotide field and highlight the different mechanisms through which the oligonucleotide-mediated gene upregulation can work, including inhibition of activity of natural antisense transcripts, interaction with promoter binding sites of noncoding regulatory RNAs, blocking of regulatory and/or miRNA binding sites in 3' UTRs, blocking splice inhibitor/enhancer sites or blocking interactions with polycomb repressive complex 2.