Modern gene therapy

Genetic mutations in the retina can be addressed by gene therapy, while robotic systems promise new surgery techniques

Dermot McGrath

Posted: Friday, December 1, 2017

Gene therapy using optical coherence tomography

Gene therapy for inherited retinal diseases is currently being validated in several clinical trials, paving the way for a potential paradigm shift in the treatment of previously incurable eye diseases, according to Dominik Fischer MD, PhD.

In a broad overview of the history and rationale for gene therapy, Dr Fischer told delegates attending the 17th EURETINA Congress in Barcelona that the retina, with its different cell populations, is an ideal target for gene replacement.

“The retina is really quite uniquely susceptible to genetic mutations. A lot can go wrong genetically speaking, and there are a whole host of mechanisms that can be targeted by genetic mutations and can lead to blindness. These genetic mutations can potentially be addressed by gene therapy, and this is why it deserves interest,” he said.

Gene therapy can work well in retinal disease stages where there is still photoreceptor function, said Dr Fischer, but it is less likely to deliver any benefit in late-stage retinal diseases where neither photoreceptor nor RPE cells are available to be transduced by gene therapy. In these cases, replacement strategies such as electronic implants or stem cell therapy are more likely to prove beneficial, he said.

The history of gene therapy stems back to the 1940s and 1950s, when researchers came to realise that it is actually the DNA that transports information that is useful and necessary for cells to have a physiological potential, said Dr Fischer. Later on, in the 1960s, investigators discovered that virus particles are very efficient in bringing DNA into cells. In ocular gene therapy as applied today, engineered viral vectors are used to bring specifically designed DNA into retinal cells that bring therapeutic benefit.

In a separate presentation focused on the present challenges and future directions of gene therapy surgery, Professor Robert MacLaren FRCOphth, FRCS, said that robotic systems are likely to transform the way gene therapy is delivered into the eye.

“The robot system that we have been using (developed by Preceyes BV) represents a great advance in gene therapy to deliver the adeno-associated viral vector containing the replacement gene. The advantage is that the movements are extremely still and precise and under the full control of the surgeon. This allows us to potentially deliver the injection over a much longer period rather than over a few seconds with manual injection,” he said.

Prof MacLaren said that refinement of surgical technique represents the next key challenge for gene therapy.

“I would say that the basic science has now been done in terms of gene therapy in the retina, but what we need to focus on now is the surgical technique of delivering the virus to make sure we get the same effects in humans that we have seen in the basic science models so far,” he said.
To inject the virus, the patient’s retina is first detached and then the virus is injected directly into the subretinal space.

There is very little margin for error with injection, said Prof MacLaren. “If we don’t get the subretinal injection right, we get reflux, intravitreal leakage and an inflammatory response,” he said.
The introduction of OCT microscopy into gene therapy surgery has greatly helped reduce the risk of over-stretching the retina, inducing inflammation and reducing the therapeutic effect, said Prof MacLaren.

“This type of tech was not available even two years ago and this really has revolutionised the surgery to ensure that there is not too much stretching of the retina,” he said.

While doubts have been expressed in some quarters about the long-term effectiveness of gene therapy treatment, Prof MacLaren said that the therapy has been shown to be effective up to at least a decade after surgery based on a single injection of the viral vector.

“The evidence we have so far from the human trials supports what we have seen in all the animal models, which is that if done correctly in the correct dose with all the cells transduced in a retina that is not irreversibly damaged, then the gene therapy treatment will be permanent,” he said.

Dominik Fischer:
Robert MacLaren: