The Landscape of Non-Viral Gene Augmentation Strategies for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are a heterogeneous group of disorders causing progressive loss of vision, affecting approximately one in 1000 people worldwide. Gene augmentation therapy, which typically involves using adeno-associated viral vectors for delivery of healthy gene copies to affected tissues, has shown great promise as a strategy for the treatment of IRDs. However, the use of viruses is associated with several limitations, including harmful immune responses, genome integration, and limited gene carrying capacity. Here, we review the advances in non-viral gene augmentation strategies, such as the use of plasmids with minimal bacterial backbones and scaffold/matrix attachment region (S/MAR) sequences, that have the capability to overcome these weaknesses by accommodating genes of any size and maintaining episomal transgene expression with a lower risk of eliciting an immune response. Low retinal transfection rates remain a limitation, but various strategies, including coupling the DNA with different types of chemical vehicles (nanoparticles) and the use of electrical methods such as iontophoresis and electrotransfection to aid cell entry, have shown promise in preclinical studies. Non-viral gene therapy may offer a safer and effective option for future treatment of IRDs

USH2A-retinopathy: From genetics to therapeutics

Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves progressive rod photoreceptor loss resulting in nyctalopia and a constricted visual field, followed by subsequent cone degeneration, leading to the loss of central vision and severe visual impairment. The USH2A gene raises many challenges for researchers and clinicians due to a broad spectrum of mutations, a large gene size hampering gene therapy development and limited knowledge on its pathogenicity. Patients with Usher type 2 may benefit from hearing aids or cochlear implants to correct their hearing defects, but there are currently no approved treatments available for the USH2A-retinopathy. Several treatment strategies, including antisense oligonucleotides and translational readthrough inducing drugs, have shown therapeutic promise in preclinical studies. Further understanding of the pathogenesis and natural history of USH2A-related disorders is required to develop innovative treatments and design clinical trials based on reliable outcome measures. The present review will discuss the current knowledge about USH2A, the emerging therapeutics and existing challenges

A Minimalist Turbulent Boundary Layer Model

We introduce an elementary model of a turbulent boundary layer over a flat surface, given as a vertical random distribution of spanwise Lamb-Oseen vortex configurations placed over a non-slip boundary condition line. We are able to reproduce several important features of realistic flows, such as the viscous and logarithmic boundary sublayers, and the general behavior of the first statistical moments (turbulent intensity, skewness and flatness) of the streamwise velocity fluctuations. As an application, we advance some heuristic considerations on the boundary layer underlying kinematics that could be associated with the phenomenon of drag reduction by polymers, finding a suggestive support from its experimental signatures.Comment: 5 pages, 10 figure

Bose-Einstein condensation for interacting scalar fields in curved spacetime

We consider the model of self-interacting complex scalar fields with a rigid gauge invariance under an arbitrary gauge group $G$. In order to analyze the phenomenon of Bose-Einstein condensation finite temperature and the possibility of a finite background charge is included. Different approaches to derive the relevant high-temperature behaviour of the theory are presented.Comment: 28 pages, LaTe

There is no new physics in the multiplicative anomaly

We discuss the role of the multiplicative anomaly for a complex scalar field at finite temperature and density. It is argued that physical considerations must be applied to determine which of the many possible expressions for the effective action obtained by the functional integral method is correct. This is done by first studying the non-relativistic field where the thermodynamic potential is well-known. The relativistic case is also considered. We emphasize that the role of the multiplicative anomaly is not to lead to new physics, but rather to preserve the equality among the various expressions for the effective action.Comment: 24 pages, RevTex, no figure

One-Loop Renormalization of a Self-Interacting Scalar Field in Nonsimply Connected Spacetimes

Using the effective potential, we study the one-loop renormalization of a massive self-interacting scalar field at finite temperature in flat manifolds with one or more compactified spatial dimensions. We prove that, owing to the compactification and finite temperature, the renormalized physical parameters of the theory (mass and coupling constant) acquire thermal and topological contributions. In the case of one compactified spatial dimension at finite temperature, we find that the corrections to the mass are positive, but those to the coupling constant are negative. We discuss the possibility of triviality, i.e. that the renormalized coupling constant goes to zero at some temperature or at some radius of the compactified spatial dimension.Comment: 16 pages, plain LATE