Implementation of guideline-directed medical therapy for heart failure patients with reduced ejection fraction in Belgium: a Delphi panel approach.

Background: The 2021 European Society of Cardiology (ESC) guidelines recommended a shift from a traditional hierarchical treatment for heart failure with reduced ejection fraction (HFrEF) to a four-pillar medical therapy strategy intended for near-simultaneous initiation. However, practical guidance for implementation in clinical practice is lacking. To address this, a Delphi Panel of 12 Belgian heart failure experts aimed to obtain consensus on integrating guideline-directed medical therapy (GDMT) in HFrEF patients in Belgian clinical practice, considering local specificities, including reimbursement criteria.

Every nano-step counts: a critical reflection on do's and don'ts in researching nanomedicines for retinal gene therapy.

Introduction: Retinal disease affects millions of people worldwide, generating a massive social and economic burden. Current clinical trials for retinal diseases are dominated by gene augmentation therapies delivered with recombinant viruses as key players. As an alternative, nanoparticles hold great promise for the delivery of nucleic acid therapeutics as well.

Together is Better: mRNA Co-Encapsulation in Lipoplexes is Required to Obtain Ratiometric Co-Delivery and Protein Expression on the Single Cell Level.

Liposomes can efficiently deliver messenger RNA (mRNA) into cells. When mRNA cocktails encoding different proteins are needed, a considerable challenge is to efficiently deliver all mRNAs into the cytosol of each individual cell. In this work, two methods are explored to co-deliver varying ratiometric doses of mRNA encoding red (R) or green (G) fluorescent proteins and it is found that packaging mRNAs into the same lipoplexes (mingle-lipoplexes) is crucial to efficiently deliver multiple mRNA types into the cytosol of individual cells according to the pre-defined ratio.

Vaccinia Virus Protein B18R: Influence on mRNA Immunogenicity and Translation upon Non-Viral Delivery in Different Ocular Cell Types.

In the last few years, interest has grown in the use of nucleic acids as an ocular therapy for retinal genetic diseases. Recently, our research group has demonstrated that mRNA delivery could result in effective protein expression in ocular cells following subretinal injection. Yet, although mRNA therapy comes with many advantages, its immunogenicity resulting in hampered mRNA translation delays development to the clinic.

Ocular barriers to retinal delivery of intravitreal liposomes: Impact of vitreoretinal interface.

Drug delivery to the posterior segment of the eye is challenging due to several anatomical and physiological barriers. Thus, there is a need for prolonged action and targeted drug delivery to treat retinal diseases. Intravitreal injections avoid anterior eye barriers, but the vitreoretinal interface and inner limiting membrane (ILM) may prevent access of drug delivery systems to the retina.

Influence of pathogenic stimuli on Müller cell transfection by lipoplexes.

Neuroprotection is a mutation-independent therapeutic strategy that seeks to enhance the survival of neuronal cell types through delivery of neuroprotective factors. The Müller cell, a retinal glial cell type appreciated for its unique morphology and neuroprotective functions, could be regarded as an ideal target for this strategy by functioning as a secretion platform within the retina following uptake of a transgene of our choice. In this in vitro study we aimed to investigate the capability of Müller cells to take up a standard liposomal vector (i.

Non-viral delivery of chemically modified mRNA to the retina: Subretinal versus intravitreal administration.

mRNA therapeutics have recently experienced a new wave of interest, mainly due to the discovery that chemical modifications to mRNA's molecular structure could drastically reduce its inherent immunogenicity and perceived instability. On this basis, we aimed to explore the potential of chemically stabilized mRNA for ocular applications. More specifically, we investigated the behavior of mRNA-loaded lipid-based carriers in human retinal cells (in vitro), in bovine retinal explants (ex vivo) and in mouse retinas (in vivo).

The obstacle course to the inner retina: Hyaluronic acid-coated lipoplexes cross the vitreous but fail to overcome the inner limiting membrane.

Considerable research over the last few years has revealed dysregulation of growth factors in various retinal diseases, such as glaucoma, diabetic retinopathy and photoreceptor degenerations. The use of messengerRNA (mRNA) to transiently overexpress a specific factor could compensate for this imbalance. However, a critical challenge of this approach lies in the ability to efficiently deliver mRNA molecules to the retinal target cells.

Müller cells as a target for retinal therapy.

Müller cells are specialized glial cells that span the entire retina from the vitreous cavity to the subretinal space. Their functional diversity and unique radial morphology render them particularly interesting targets for new therapeutic approaches. In this review, we reflect on various possibilities for selective Müller cell targeting and describe how some of their cellular mechanisms can be used for retinal neuroprotection.

Morphology and Composition of the Inner Limiting Membrane: Species-Specific Variations and Relevance toward Drug Delivery Research.

The inner limiting membrane (ILM) represents the structural boundary between the vitreous and the retina, and is suggested to act as a barrier for a wide range of retinal therapies. While it is widely acknowledged that the morphology of the human ILM exhibits regional variations and undergoes age-related changes, insight into its structure in laboratory animals is very limited. Besides presenting a detailed overview of the morphology and composition of the human ILM, this review specifically reflects on the species-specific differences in ILM structure.

Search for the Source of the Retinal Relaxing Factor.

Unlabelled: Purpose/Aim of the study: the retinal relaxing factor (RRF) is an unidentified paracrine factor, which is continuously released from retinal tissue and causes smooth muscle cell relaxation. This study tried to identify the cellular source of the RRF. Furthermore, the possible RRF release by voltage-dependent sodium channel activation and the calcium-dependency of the RRF release were investigated.

In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye.

Many ocular disorders leading to blindness could benefit from efficient delivery of therapeutics to the retina. However, despite extensive research into drug delivery vehicles and administration techniques, efficacy remains limited because of the many static and dynamic barriers present in the eye. Comprehension of the various barriers and especially how to overcome them can improve our ability to estimate the potential of existent drug delivery vectors and support the design of new ones.

Toward smart design of retinal drug carriers: a novel bovine retinal explant model to study the barrier role of the vitreoretinal interface.

Retinal gene delivery via intravitreal injection is hampered by various physiological barriers present in the eye of which the vitreoretinal (VR) interface represents the most serious hurdle. In this study, we present a retinal explant model especially designed to study the role of this interface as a barrier for the penetration of vectors into the retina. In contrast to all existing explant models, the developed model is bovine-derived and more importantly, keeps the vitreous attached to the retina at all times to guarantee an intact VR interface.

Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger.

In the field of nonviral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known that the introduction of IVT mRNA into mammalian cells elicits an innate immune response that has favored mRNA use toward immunotherapeutic vaccination strategies. However, for non-immunotherapy-related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, because it can seriously compromise the expression of the desired protein.