Suprachoroidal Delivery of Viral and Nonviral Gene Therapy for Retinal Diseases

Abstract

Retinal gene therapy is a rapidly growing field with numerous clinical trials underway, and route of delivery is a critical contributor to its success. Subretinal administration, which involves pars plana vitrectomy in the operating room, offers targeted delivery to retinal-pigment epithelium cells and photoreceptors. Due to the immune-privileged nature of the subretinal space, the risk of an immune reaction against viral capsid antigens is minimized, an advantage of subretinal administration in patients with preexisting neutralizing antibodies. Intravitreal administration, with fewer procedure-related complications, is challenged by potential immune response and incomplete vector penetration through the internal limiting membrane. However, novel vectors, optimized by ''directed evolution'' may address these issues. Nonsurgical in-office suprachoroidal gene delivery offers the potential for greater surface-area coverage of the posterior segment compared to focal subretinal injection, and is not hindered by the internal limiting membrane. However, the vector must pass through multiple layers to reach the targeted retinal layers, and there is a risk of immune response. This review highlights recent developments, challenges, and future opportunities associated with viral and nonviral suprachoroidal gene delivery for the treatment of chorioretinal diseases. While ocular tolerability and short-term effectiveness of suprachoroidal gene delivery have been demonstrated in preclinical models, durability of gene expression, long-term safety, potential systemic exposure, and effective delivery to the macula require further exploration. Although the safety and efficacy of suprachoroidal gene delivery are yet to be proven in clinical trials, further optimization could facilitate nonsurgical in-office suprachoroidal gene therapy.

Biomechanics of suprachoroidal drug delivery: From benchtop to clinical investigation in ocular therapies

“…Microneedles are made to the length of the approximate thickness of the sclera, and are used with a custom injector specifically designed for suprachoroidal drug delivery [3][4][5][6][7]. While there are some challenges with this type of suprachoroidal injection procedure, including the lack of direct intraoperative visualization and the potential need for customized injectate formulations that are compatible with the device [26,32], to date, the procedure has been performed over 1,000 times in clinical trial patients with an acceptable safety profile [33]. Suprachoroidal injection using proprietary microneedlebased technology, the SCS Microinjector ® (Clearside Biomedical, Alpharetta, GA) consists of three key steps, unique from other ocular injections.…”

Suprachoroidal Delivery of Small Molecules, Nanoparticles, Gene and Cell Therapies for Ocular Diseases

“…The standard for ocular gene therapy administration is subretinal injection, a highly-specialized surgical procedure, which is generally performed at selected Centers of Excellence, given the potential complications of pars plana vitrectomy associated procedures such as retinotomy [ 78 , 79 ]. Suprachoroidal gene delivery, an alternative route of administration, has demonstrated promise preclinically and is currently undergoing clinical evaluations [ 80 ]. Delivery of gene therapy via SC injection enables an in-office gene therapy administration and may facilitate increased patient access as well as reduced procedural risks compared to subretinal delivery.…”

<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

“…However, the suprachoroidal space is not anatomically immune privileged and the presence of choriocapillaris causes rapid clearance of the administered drug hindering effective transduction of the retina. 96 The Choice of AAV Vector AAV, a parvovirus, has a protein capsid surrounding a DNA genome (single stranded) approximately 4.8 kb in size. The genome contains genes responsible for replication, capsid, and assembly.…”