Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.

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Adeno-associated virus vector as a platform for gene therapy delivery

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood–retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

Ocular Drug Delivery

Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CBSB-hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21–24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 × 1010 vector genomes in 150 μl and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic tox...

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Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

Gene therapy returns to centre stage

Supplemental Digital Content is Available in the Text. Abstract: Emerging monoclonal antibody therapies are assuming greater importance in the management of severe and refractory forms of immunity-driven and oncological disorders. However, some have been found to induce adverse ocular events (AOEs) leading to discontinuation of treatment or additional multidisciplinary management. We present the current knowledge concerning AOEs associated with 3 monoclonal antibody therapies: dupilumab, tralokinumab, and belantamab mafodotin. We examine the manifestations of their AOEs, proposed pathophysiological mechanisms, and current treatment recommendations. We identified and reviewed all studies for dupilumab, tralokinumab, and belantamab mafodotin using the keywords “dupilumab,” “tralokinumab,” “belantamab mafodotin,” “conjunctivitis,” and “keratopathy” from January 2016 to November 2021. Conjunctivitis was the most frequently reported AOE in patients with atopic dermatitis receiving dupilumab or tralokinumab. Mild cases were managed with warm compresses for associated meibomian gland dysfunction, artificial tears, and antihistamine/mast cell stabilizer eye drops. In more severe cases, additional anti-inflammatory therapy, with corticosteroid eye drops or ointments, or topical calcineurin inhibitors—such as tacrolimus or ciclosporin—were required. Patients with resistant or refractory multiple myeloma treated with belantamab mafodotin often developed keratopathy, which could necessitate contact lens fitting, or for cycles of belantamab mafodotin to be delayed.

https://journals.lww.com/corneajrnl/Fulltext/9900/Dupilumab_Induced,_Tralokinumab_Induced,_and.193.aspx

Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin–Induced Adverse Ocular Events—Incidence, Etiology, and Management

Absence Of Ocular Malignant Transformation After Subretinal Delivery Of Raav2/2 Or Hiv-1 Vectors In P53 Knockout Mice

Visually-Guided Mobility in Patients Treated With Gene Therapy for Leber's Congenital Amaurosis

Editor

We thank Konstantopoulos et al for their interest in our paper and congratulate them for having conducted such a large study. It should be noted, however, that we did not actually conclude that older age was not associated with an increased risk …

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Authors’ response to Konstantopoulos et al

B MJ published an article regarding management strategies for acute infective conjunctivitis.1 This study reached a similar conclusion to the study abstracted in EBM.2 Both studies are not clear in the method by which a diagnosis of conjunctivitis is made, in particular how viral and bacterial cases are differentiated.

Viral conjunctivitis follows a distinct pattern …

https://ebm.bmj.com/content/ebmed/12/3/93.full.pdf

Scott J Robbie

Papers

Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin–Induced Adverse Ocular Events—Incidence, Etiology, and Management

Absence Of Ocular Malignant Transformation After Subretinal Delivery Of Raav2/2 Or Hiv-1 Vectors In P53 Knockout Mice

Visually-Guided Mobility in Patients Treated With Gene Therapy for Leber's Congenital Amaurosis

Authors’ response to Konstantopoulos et al

Viral infections need to be excluded from the cohort for the results to be truly meaningful.