Translational Retinal Research and Therapies.

The following review summarizes the state of the art in representative aspects of gene therapy/translational medicine and evolves from a symposium held at the School of Veterinary Medicine, University of Pennsylvania on November 16, 2017 honoring Dr. Gustavo Aguirre, recipient of ARVO's 2017 Proctor Medal. Focusing on the retina, speakers highlighted current work on moving therapies for inherited retinal degenerative diseases from the laboratory bench to the clinic

Reply to Townes-Anderson: RPE65 Gene Therapy Does Not Alter the Natural History of Retinal Degeneration

We appreciate the interest shown by TownesAnderson in our article examining the natural history of retinal degeneration in Leber congenital amaurosis caused by retinal pigment epithelium-specific protein 65kDa (RPE65) mutations and evaluating the consequences of gene augmentation therapy. Townes-Anderson’s remarks focused on the final phrase of the last sentence of the Discussion of our article. In the full sentence, we suggested that in the future, agents to reduce cell death could be delivered in combination with a more advanced version of the gene augmentation therapy that reaches not only remaining rods and extrafoveal cones but also foveal cone photoreceptors

Improvement in Vision: A New Goal for Treatment of Hereditary Retinal Degenerations

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention

Calcium Channel Blocker D-\u3cem\u3ecis\u3c/em\u3e-Diltiazem Does Not Slow Retinal Degeneration in the \u3cem\u3ePDE6B\u3c/em\u3e Mutant \u3cem\u3ercd1\u3c/em\u3e Canine Model of Retinitis Pigmentosa

Purpose: D-cis-diltiazem, a calcium channel blocker, has been reported to enhance photoreceptor survival in the rd mouse, a model of retinitis pigmentosa (RP) resulting from mutation of the PDE6B gene. We tested the hypothesis that diltiazem treatment would similarly rescue the canine rcd1 model of RP, which is also caused by a null mutation in the PDE6B gene. Methods: D-cis-diltiazem was delivered orally twice daily to rcd1 affected dogs beginning at 4 weeks of age; untreated age-matched rcd1 dogs served as controls. At 14 weeks, electroretinograms (ERG) were performed on all animals; 14 dogs were euthanized at this age, and 2 dogs at 25 weeks of age. Eyes were enucleated, fixed, and processed for routine histological examination. Results: No significant differences were found in ERG or histopathologic parameters between diltiazem-treated and untreated rcd1 dogs. Neither rcd1 group showed a rod b-wave; ERGs evoked by single white flashes (dark- or light-adapted) and flicker were also identical between groups. Similarly, treated and untreated animals did not differ in the degree of preservation of the photoreceptor layer, confirmed in cell counts within the outer nuclear layer. Conclusions: Treatment of rcd1 affected dogs with D-cis-diltiazem did not modify the photoreceptor disease when results were assessed using either ERG or histopathologic criteria. The positive photoreceptor-rescue effect of calcium channel blockers reported in the rd mouse was thus not generalizable to another species with retinal degeneration due to mutation in the PDE6B gene. Caution needs to be exerted in extrapolation to the comparable human forms of RP

New variables, the gravitational action, and boosted quasilocal stress-energy-momentum

This paper presents a complete set of quasilocal densities which describe the stress-energy-momentum content of the gravitational field and which are built with Ashtekar variables. The densities are defined on a two-surface $B$ which bounds a generic spacelike hypersurface $\Sigma$ of spacetime. The method used to derive the set of quasilocal densities is a Hamilton-Jacobi analysis of a suitable covariant action principle for the Ashtekar variables. As such, the theory presented here is an Ashtekar-variable reformulation of the metric theory of quasilocal stress-energy-momentum originally due to Brown and York. This work also investigates how the quasilocal densities behave under generalized boosts, i. e. switches of the $\Sigma$ slice spanning $B$. It is shown that under such boosts the densities behave in a manner which is similar to the simple boost law for energy-momentum four-vectors in special relativity. The developed formalism is used to obtain a collection of two-surface or boost invariants. With these invariants, one may ``build" several different mass definitions in general relativity, such as the Hawking expression. Also discussed in detail in this paper is the canonical action principle as applied to bounded spacetime regions with ``sharp corners."Comment: Revtex, 41 Pages, 4 figures added. Final version has been revised and improved quite a bit. To appear in Classical and Quantum Gravit

The Standard Model with gravity couplings

In this paper, we examine the coupling of matter fields to gravity within the framework of the Standard Model of particle physics. The coupling is described in terms of Weyl fermions of a definite chirality, and employs only (anti)self-dual or left-handed spin connection fields. It is known from the work of Ashtekar and others that such fields can furnish a complete description of gravity without matter. We show that conditions ensuring the cancellation of perturbative chiral gauge anomalies are not disturbed. We also explore a global anomaly associated with the theory, and argue that its removal requires that the number of fundamental fermions in the theory must be multiples of 16. In addition, we investigate the behavior of the theory under discrete transformations P, C and T; and discuss possible violations of these discrete symmetries, including CPT, in the presence of instantons and the Adler-Bell-Jackiw anomaly.Comment: Extended, and replaced with LaTex file. 25 Page

BF Actions for the Husain-Kuchar Model

We show that the Husain-Kuchar model can be described in the framework of BF theories. This is a first step towards its quantization by standard perturbative QFT techniques or the spin-foam formalism introduced in the space-time description of General Relativity and other diff-invariant theories. The actions that we will consider are similar to the ones describing the BF-Yang-Mills model and some mass generating mechanisms for gauge fields. We will also discuss the role of diffeomorphisms in the new formulations that we propose.Comment: 21 pages (in DIN A4 format), minor typos corrected; to appear in Phys. Rev.

Superalgebra and Conservative Quantities in N=1 Self-dual Supergravity

The N=1 self-dual supergravity has SL(2,C) and the left-handed and right -handed local supersymmetries. These symmetries result in SU(2) charges as the angular-momentum and the supercharges. The model possesses also the invariance under the general translation transforms and this invariance leads to the energy-momentum. All the definitions are generally covariant . As the SU(2) charges and the energy-momentum we obtained previously constituting the 3-Poincare algebra in the Ashtekar's complex gravity, the SU(2) charges, the supercharges and the energy-momentum here also restore the super-Poincare algebra, and this serves to support the reasonableness of their interpretations.Comment: 18 pages, Latex, no figure