A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.

Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6ßrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Techniques for subretinal injections in animals.

Subretinal injections are not commonly performed during clinical treatment of animals but are frequently used in laboratory animal models to assess therapeutic efficacy and safety of gene and cell therapy products. Veterinary ophthalmologists are often employed to perform the injections in the laboratory animal setting, due to knowledge of comparative ocular anatomy between species and familiarity with operating on non-human eyes. Understanding the different approaches used for subretinal injection in each species and potential complications that may be encountered is vital to achieving successful and reproducible results. This manuscript provides a summary of different approaches to subretinal injections in the most common animal model species, along with information from published literature and experience of the authors to educate novice or experienced surgeons tasked with performing these injections for the first time.

Manifestations of systemic disease in the retina and fundus of cats and dogs.

The fundus is unique in that it is the only part of the body that allows for a noninvasive and uninterrupted view of vasculature and nervous tissue. Utilization of this can be a powerful tool in uncovering salient incidental findings which point to underlying systemic diseases, and for monitoring response to therapy. Retinal venules and arterioles allow the clinician to assess changes in vascular color, diameter, outline, and tortuosity. The retina and optic nerve may exhibit changes associated with increased or decreased thickness, inflammatory infiltrates, hemorrhages, and detachments. While some retinal manifestations of systemic disease may be nonspecific, others are pathognomonic, and may be the presenting sign for a systemic illness. The examination of the fundus is an essential part of the comprehensive physical examination. Systemic diseases which may present with retinal abnormalities include a variety of disease classifications, as represented by the DAMNIT-V acronym, for Degenerative/Developmental, Anomalous, Metabolic, Neoplastic, Nutritional, Inflammatory (Infectious/Immune-mediated/ischemic), Toxic, Traumatic and Vascular. This review details systemic illnesses or syndromes that have been reported to manifest in the fundus of companion animals and discusses key aspects in differentiating their underlying cause. Normal variations in retinal anatomy and morphology are also considered.

Consensus guidelines for nomenclature of companion animal inherited retinal disorders.

Companion animals, namely dogs, cats, and horses, can be affected with many forms of hereditary retinal disease. The number of such diseases characterized in the last decade has increased substantially, and nomenclature is nonstandardized, heterogenous, and confusing. We provide in this viewpoint article consensus guidelines for naming of companion animal hereditary retinal diseases, either prospectively or retrospectively. These consensus guidelines have been developed with the purpose of standardizing nomenclature. We provide examples for the iterative nomenclature process and a comprehensive File S1 on proposed renaming of previously described diseases.