At the cutting edge of gene therapy treatment

A new era approaches in the treatment of inherited retinal diseases

Leigh Spielberg

Posted: Monday, March 1, 2021

“The introduction of retinal gene therapy into the clinic has been a major game changer in the field of ophthalmic genetics,” said Professor Camiel Boon MD, PhD, of Amsterdam University Medical Centres and Leiden University Medical Centre.

Dr Boon, who is a Professor of Ophthalmology and Clinical Ophthalmic Genetics, is an expert on retinal dystrophies and works on the cutting edge of this blossoming and dynamic field.

This major therapeutic advance has been received as excellent news to those of us who have ever had to gently suggest to a patient with an inherited retinal disease (IRD) that there is little hope of ever recovering lost vision or even maintaining what they currently have.

Inherited retinal diseases include retinal dystrophies, which are chronic, progressive disorders and include diseases such as Leber’s congenital amaurosis and retinitis pigmentosa. They are collectively caused by mutations in over 200 different genes, and had previously been considered untreatable. Recent advances such as the prospect of gene therapy, however, have been providing hope.

“Voretigene neparvovec (Luxturna, Spark Therapeutics) heralds a new era, both for retinal dystrophies specifically and for human gene therapy in general,” said Dr Boon, referring to the novel gene therapy for patients with vision loss due to biallelic RPE65 mutation-associated retinal dystrophies who have sufficient viable retinal cells. The genetic material is delivered into retinal cells via an adeno-associated virus (AAV) vector, which is injected subretinally.

The introduction of voretigene neparvovec has been widely reported, and many patients are now aware of the possibilities available.

Professor Bart Leroy agrees. “The initial success of gene therapies using AAV vector systems, as well as novel technologies such as antisense oligonucleotides, represent major breakthroughs. We have first-hand experience with both, and these successes have led to an explosion of clinical trials for a multitude of IRDs, which will hopefully benefit our patients as soon as possible.”

Dr Leroy MD, PhD, is an ophthalmologist and clinical geneticist who splits his time between the Ghent University Hospital in Belgium, where he is chairman of the ophthalmology department, and Professor of Ophthalmology & Ophthalmic Genetics, and The Children’s Hospital of Philadelphia (CHOP), where he is director of the Ophthalmic Genetics & Retinal Degenerations Clinics. Voretigene neparvovec was developed by Spark Therapeutics and the team at CHOP.

But those on the cutting edge are not content to rest on their laurels. Professor Leroy said that, “Apart from the classic AAV-mediated gene augmentation therapies, I’m very much looking forward to an era of other custom treatments becoming more widely available. These include antisense oligonucleotide therapies, which act as a molecular patching technique at the RNA level, and CRISPR/Cas9 gene editing, as well as generic gene therapies where artificial photoreception is induced using photosensitive pigment genes ectopically expressed in the remaining bipolar or ganglion cells of the retina of IRD patients.”

Professor Boon also drew attention to the rapid advances currently being made in patient-derived induced pluripotent stem cell-based retinal organoids.

“These represent a huge advantage as a personalised in-vitro disease model that can be used to test all manner of genetic treatment strategies,” he said.

The advances have not been limited to therapeutics; diagnostics and follow-up modalities have also further been refined. Dr Leroy explained: “Blue and near-infrared light autofluorescence (BAF & NIRAF) imaging are the mainstay of imaging of IRDs, and their importance cannot be overestimated. Indeed, these techniques allow one to evaluate evolution of disease with or without functional testing. In addition, optical coherence tomography remains essential to estimate whether outer retinal cells are still present in sufficient numbers for gene therapies to be beneficial.”

But how are the results of these therapies evaluated? In other words, how do we quantify the results? Identifying reliable clinical outcome measures to assess the efficacy of gene therapy will also remain the focus of many researchers’ attention.

Professor Leroy clarified this for me: “Fullfield sensitivity testing has emerged as a straightforward outcome measure to evaluate effects of genetic therapies, and correlates well with more time-consuming outcome measures such as multi-luminance mobility testing (MLMT).” Dark-adapted chromatic perimetry and microperimetry have also proven their value, he added.

Dr Boon is not yet satisfied. “But we also have a strong need for more patient-reported outcome measures as well as more large-scale natural history studies, both retrospective and prospective, for more information on the diseases’ natural course and prognoses,” he said.

Dr Boon pointed out that such large-scale European collaborations represent a great example of how investigator-initiated research can also help to implement gene therapy in the clinic by delineating IRDs, their clinical characteristics and their natural history. Dr Boon is involved in a range of such multi-centre natural history studies with both national reach (the Dutch RD5000 Expertise Centre Database) and international stature such as the European Reference Network for Rare Eye Disease (ERN-EYE). Dr Leroy is also involved in ERN-EYE and the European Retinal Disease Consortium (ERDC) and European Retinal Treatment Consortium (ERTC).

Both are also very enthusiastic about the rapidly evolving digital support systems that may help patients with severe vision loss, such as the OrCam MyEye, a voice-activated device that attaches to the wearer’s glasses and conveys visual information audibly in real time.

“We are currently performing studies on the usefulness of such aids in IRD patients,” said Dr Boon.

And what keeps retinal dystrophy researchers like Professors Leroy and Boon up at night? What are the challenges that lie ahead?

“A major diagnostic problem is that we’re still unable to locate the causative gene in a sizeable number of patients, despite the use of the newest DNA diagnostics techniques such as whole-genome sequencing. This means that up to 30% of recessive retinitis pigmentosa cases remain unsolved,” said Dr Boon.

“Here lies a big future challenge in the field: how to find the causal gene in the big and complex soup of genes and more ‘obscure’ genetic regions in our human genome,” he asked. “This is a problem that will have to be solved by bio informatics,” computer-based calculations that will be able to identify the offending gene.

Professor Leroy, however, seems hopeful. “With the advent of easily accessible broad spectrum genetic screening, we are now picking up more pathogenic variants in genes than ever before in patients with IRDs.”

I asked Professor Leroy whether there are interesting therapeutic options that have been developed or are in testing or due for approval sometime soon. “I believe we’ll be seeing new viral vectors which are more efficient in transfecting the outer retinal cells even after intravitreal injection,” rather than only via subretinal injection. “Indeed, subretinal injections for photoreceptor or RPE-based disease are both more difficult and cause more complications than administration via an intravitreal approach.”

Dr Boon suggested that, despite the major strides that have been made and the further advances that we can expect, the maxim of “under-promise and over-deliver” still applies. Nevertheless: “It’s a great time to work in this rapidly-evolving, cutting-edge research field.” Indeed, “The conversations that I have with patients in my ophthalmic genetics clinic have recently changed considerably, because many patients are eager to know more about these hopeful developments.”

“I would certainly say that since we have now reached the era of interventional therapies for rare disorders such as IRDs, never has there been a more exciting time to be in ophthalmic genetics,” concluded Professor Leroy.

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