A Review of Personalised Molecular Medicine for the Treatment of Corneal Disorders

As the field of molecular medicine evolves greater numbers of systems are being utilised to ellicit changes in gene expression in an attempt to resolve genetic or environmental disorders.Within this review we focus on 4 of the more common forms of gene therapy utilised to alter gene expression; siRNAs, TALENs, ZFNs and CRISPR/Cas9.Short-interfering RNAs (siRNAs) are one method of transiently down regulating the expression of any target gene through the exploitation of the RNA interference pathway, often referred to as gene silencing [1].The bacterial Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing system is the latest method of interrupting gene expression through cleavage of target DNA.Its effectiveness at cleaving genomic DNA in mammalian cells in vitro and in vivo [2,3], the specificity that this system exhibits [4, 5] and the relative ease with which targeted systems can be constructed [6], make this method of gene disruption a favourable technique.Transcription activator-like effector nucleases (TALENs) are artificial systems that can be designed and constructed relatively quickly to bind practically anywhere in the genome and cleave double stranded DNA, thus interrupting the expression of any given target gene AbstractThe cornea represents an ideal tissue to elucidate the potential of molecular medicine to treat genetic disorders.It is a small, readily accessible tissue that is easy to monitor treat topically, while a number of corneal disorders are well characterized with regard to a known genetic cause.In addition, due to their genetic basis most of these conditions are bilateral, affecting both corneas, allowing for a clear comparison between treated and untreated tissue using the fellow eye as a control.Currently, molecular techniques utilising siRNAs, CRISPR/Cas9, TALENS and ZFNs are being evaluated by many for their therapeutic potential for corneal disorders.Methodologies are discussed within this review with particular emphasis on the more recent and emerging field of CRISPR/Cas9-based therapeutics.Since the advent of gene therapies, effective delivery has been a challenge.Potential ocular delivery techniques include viral vectors, nanoparticles or physical injection.Studies employing in vitro and in vivo models of corneal disorders have demonstrated promising results for treatment by molecular techniques.However, many of these studies have not translated into the clinic, perhaps due to a lack of good animal models for preclinical testing or failure to develop suitable delivery methods.Until this occurs it is difficult to fully gauge the usefulness of these techniques to treat corneal disorders in human patients over a sustained time period.Here we present a review of current research into molecular-based therapies for genetic corneal disorders and discuss the applicability of these studies to advancing translational research for other genetic disorders.

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