Swimming Against the Nucleotides

The Test of Time

Reflecting on the past – and future – of gene therapy

My interest in inherited retinal disease (IRD) began in 2001, with my research degree. I had always been passionate about retinal disease, but I found IRDs to be even more fascinating. There are over 300 known diseases, each one heterogeneous – both clinically and genetically. Despite this, the IRD field remains at the forefront of innovation, with novel treatment types and increasing understanding of underlying disease mechanisms.

The biggest transformation I have seen in my 20 years in the field has been our ability to definitively establish a genetic diagnosis. We have gone from being able to molecularly characterize a minority of patients to being able to characterize the majority. We have also gone from relatively low-level resolution to ultra-high-resolution imaging – so much so that we are now at the point where we can image individual retinal cells in unprecedented detail using adaptive optics imaging. Of course, you cannot have a conversation about change without acknowledging the huge technological advancements that have occurred in the multiple avenues of intervention being investigated, especially in gene therapy. In my mind, these three developments have conspired to create the ideal landscape for establishing treatments for IRD.

Today, my research interests include novel gene identification, molecularly characterizing patients to establish their genetic diagnosis, and natural history studies in order to perform state-of-the-art deep phenotyping to optimize clinical trial design and participant stratification. I’m currently a PI on four gene therapy trials for (i) Achromatopsia caused by CNGB3; (ii) Achromatopsia caused by CNGA3; (iii) X-linked retinitis pigmentosa caused by RPGR, and (iv) RPE65 associated retinopathy; as well as a gene therapy study of Leber Congenital Amaurosis caused by AIPL1 – all sponsored by MeiraGTx. This illustrates the importance of funding – there is no doubt that increased resource will facilitate further advancements in therapeutic avenues. Running trials is a multi-million-dollar endeavor, and the regulation surrounding them is onerous, slow and multi-faceted. This requires funding through a commercial partner. This undoubtedly is accelerating the rate of development, and the number of clinical trials is increasing exponentially.

Although we have seen wonderful progress over the last decade, there will be further iterative improvements. However, one of the greatest challenges to clinicians and researchers in the gene therapy field is to develop therapies for autosomal dominant disease and create more sophisticated and reliable gene-editing approaches.

In the next five years, we should have at least half a dozen phase-three gene therapy trials ongoing and at least two to three more approved therapies. The dream outcome, of course, would be to establish an intravitreal gene therapy. Unlike sub-retinal delivery methods, this would be more readily delivered, however it is not yet an effective route of delivery. Gene therapy is currently the most advanced therapeutic avenue, compared to cellular therapies, neuroprotection or artificial vision. Intervening earlier, often in childhood, will likely result in our patients deriving greater benefits.