Instead of relying on traditional drug modalities, gene therapies rely on delivery of nucleic acids into patient’s cells to prevent, slow, stop or treat diseases. In the past decades, gene therapy has been broadly studied in pre-clinical and clinical trials. Adeno-associated virus (AAV) vectors rely on a small non-pathogenic viral shell for gene delivery. To date, several AAV vector drugs have achieved the approval of the United States Food and Drug Administration for the treatment of rare monogenetic diseases. The first of these such drugs, Luxterna, is now utilized in the posterior eye for the treatment of a rare form of inherited blindness. However, to date no AAV-based gene drugs have been applied to treat blindness resulting from diseases in the anterior eye. Interestingly, AAV vector administration to anterior eye includes several options and in the present study, we investigated AAV gene delivery by multiple capsid serotypes to multiple ocular and periocular compartments following subconjunctival (SC) injection, which is relatively simple and safe without resultant ocular tissue damage.

Fig. 1. Representative images of AAV mediated GFP fluorescence in eye muscle and cornea.

不同的确定AAV治疗的效用us ocular disorders following SC injection, we performed a survey in mice with several natural AAV capsids. First, injection tolerability was evaluated following SC injection of a dye to monitor distribution. No safety concerns were noted with dye dispersion observed primarily in the periocular tissues with no obvious penetration in the eye. In contrast, following AAV vector injection, the transduction efficiency and vector distribution was AAV serotype dependent in several tissues including the eye lid, conjunctiva, and cornea, as well as the periocular tissues including eye muscles (Fig. 1). One of the most striking findings is related to discrete cell transduction in the cornea; AAV serotype 6 (AAV6) vectors appeared restricted to the corneal endothelium layer while AAV8 particles transduced the corneal stromal layer specifically (Fig. 1).

The results indicated that, depending on the target tissue involved in anterior ocular diseases, the choice of the AAV serotype and the suitability of the SC injection should be taken into consideration. For example, for corneal lysosomal storage diseases, in which the corneal stromal layer involved, one may consider using AAV8. Alternatively, for treatment of Fuch’s dystrophy which is due to deficiencies in the corneal endothelial layer, AAV6 vectors administrated via SC injection may be a prudent choice as they transduce the only relevant corneal cell type. Collectively, the data herein serve as a foundation for selection and the further development of AAV vectors for ocular disorders following a simple and safe SC injection.

Liujiang Song, Matthew Hirsch
Department of Ophthalmology and Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Publication

Serotype survey of AAV gene delivery via subconjunctival injection in mice.
Song L, Llanga T, Conatser LM, Zaric V, Gilger BC, Hirsch ML
Gene Ther. 2018 Sep

Read offline:

Related Articles:

	What treatment is really medically and economically…Currently, direct-acting agent (DAA) therapies have high efficacy and safety and are the main strategy to eliminate hepatitis C virus (HCV) worldwide. Some DAA therapies are also effective for HCV-infected…
	Orexin-A regulates dopamine D2 receptor in the mesolimbic…Orexin-A (orx-A) is a neuropeptide expressed exclusively in hypothalamic neurons. Orx-A acts through the activation of type-1 (Orx1R) and -2 (Orx2R) receptors present in the mesolimbic circuit and in other…
	Gas types affect stability of microbubbles and ultrasound…Ultrasound (US) is used for clinical diagnosis and therapy. Microbubbles (MBs) as US-contrast agents are applied to detect micro blood flow or specific lesions. Recently, the combination of MBs and…
	Intracranial injections and animal models: towards…The use of laboratory animals helped us to better understand a myriad of biological processes in health and disease and enabled the development of therapies that effectively cure, or ameliorate…
	Your pharmacist will see you now!Public perception of pharmacists might be limited to dispensing medications. However, pharmacists are trained to deliver patient care to help patients improve their health-related outcomes and achieve their goals. Recognizing…
	Atmospheric and genetic parameters influence Rhinovirus…Rhinoviruses are a diverse set of very small and common viruses, repeatedly infecting humans in the course of a single year. For most people, infection usually results in mild common…