Professor Hardcastle and her colleagues in the UK Inherited Retinal Dystrophy Consortium (UKIRDC), which is funded by Retina UK, have been using cutting edge technology to read through the entire genetic code of hundreds of people with inherited sight loss and pick out newly identified changes that could be causing problems. The consortium has brought together scientists with complementary fields of expertise from leading UK centres.
Professor Hardcastle explained: “This has enabled us to create an efficient infrastructure where we can share the clinical information and the genetic data and all our combined knowledge and expertise so we can have really informed discussions and try and interpret what’s going on in the genomes (full genetic codes). This has been very successful; we’ve discovered many new genes and different variants that we weren’t expecting.”
Professor Hardcastle also explained how she is using stem cell technology to create living models of the retina in the lab, enabling her team to better understand the damage caused by a particular genetic fault and investigate ways to fix the problem. She went on to say: “We can now edit genes, so when we’ve got the stem cells we can actually edit the DNA and make mutants (to replicate disease) or actually try and cure the mistake by correcting it. This is proving to be an incredible tool; the limit here is just your imagination in terms of what we can do.”
Towards treatments
Meanwhile, Dr de Silva provided a whistle-stop tour of the various treatment approaches being explored.
“It’s really a testament to the huge amount of work that’s going on in this area that I’ve got quite a lot to talk about” she told us.
Gene replacement therapy
This generally involves using a harmless virus to carry healthy copies of the affected gene into retinal cells. One such therapy, Luxturna, is already available on the NHS to treat sight loss caused by faults in the RPE65 gene; others are progressing steadily through clinical trials, including those for X-linked RP (RPGR gene), choroideremia and achromatopsia. These therapies target specific genes, so a genetic test result would be essential to determine eligibility, and can only work in surviving photoreceptors, so relatively early in the progression of a condition.
Antisense oligonucleotides / RNA therapy
This approach could be used to treat conditions inherited via an autosomal dominant pattern, or those caused by faults in very large genes, where gene replacement therapy can be challenging. It involves creating special molecular “patches” to cover up a faulty section of genetic code, enabling the retinal cell to read around the fault and produce a protein that still works to some degree. This is another highly specific approach requiring a genetic test result and a reasonable proportion of surviving retinal cells. It’s undergoing clinical trials for Usher syndrome (USH2A gene), LCA type10 (CEP290 gene) and autosomal dominant RP (RHO gene).
Gene editing
This uses a biological tool called CRISPR to snip out and correct specific spelling mistakes in the genetic code. Like RNA therapy, it could potentially be useful for addressing faults in very large genes like USH2A and ABCA4, which are associated with many cases of Usher syndrome and Stargardt disease respectively. It has reached early stage clinical testing for LCA type10.
Oral medications
All of the approaches mentioned so far are administered via injection into the eye. However, it may be possible to treat some conditions with medicines that reduce the build-up of toxic substances that can occur in retinal cells when certain genes and proteins malfunction. This approach is undergoing clinical testing in Stargardt disease.
Stem cells
Retinal progenitor cells are “baby” retinal cells that have yet to fully mature into specialist photoreceptors. Researchers are carrying out clinical trials to see whether injecting them into the eye can provide the existing cells with nourishment and support, or even if they can take over some of the work. This treatment doesn’t require a specific genetic diagnosis, but the results of the clinical trials will help determine whether stem cell therapy is most helpful at any particular stage of sight loss.
Optogenetics
A number of research groups and biotechnology companies are investigating this exciting approach for treating the later stages of sight loss, when vision is minimal. It involves providing cells in the retina that don’t normally sense light but are unaffected by the disease process, with genetic instructions for building light sensitive proteins. These cells can then respond to light and send simple images to the brain. This could provide limited perception of objects, perhaps restoring some independent mobility to a person with severe sight loss, but would not enable reading, TV viewing etc. Many optogenetics systems would require the use of special glasses / goggles. Read more about the most recent developments in optogenetics.
The clinical trials process is long, and it could be a few more years before we see more treatments become available in the NHS, but with so many avenues being explored, there is a huge amount of hope for the future.