The Promise of GENE THERAPY

BY VICKI FRYE

Bringing hope to patients with inherited retinal disease

INHERITED RETINAL DEGENERATIONS are genetic diseases that cause irreversible blindness. Developing treatments for these conditions is a challenging task, particularly because they are caused by mutations in over 300 genes that lead to varying types and severity of vision loss.

Historically there has been no cure for inherited retinal degenerations. Recent innovations in research have provided a promising type of treatment called gene therapy. This approach aims to correct defective genes by replacing them with healthy ones.

Bench to Bedside

The introduction of gene therapy to practical ophthalmology is a remarkable example of how a complex human disease can be addressed by combined efforts of scientists and clinicians. A “bench-to-bedside” approach highlights the tremendous efforts of laboratory research teams behind the development of groundbreaking medications.

One particularly severe type of inherited blindness is Leber’s congenital amaurosis, which impacts children at a young age. The first breakthrough in understanding the cause of blindness for those with Leber’s was in the 1990s, when scientists discovered that the disease arises from an error in the RPE65 gene. This set the stage to take action against this disease.

During the same time another group of scientists found that the same gene, RPE65, is affected in a group of dogs who are blind. This discovery led to an unprecedented opportunity to determine if supplying these dogs with a healthy RPE65 gene would enable them to regain vision.

Left to right front row: Natasha Klementeva, PhD, Lauren Cao, BS, Lin Yu, PhD, Stella Finkelstein, MS, Carson Castillo, MS, Margaux Kreitman, PhD, Vadim Arshavsky, PhD.

A few years later, a dog named Lancelot made an unusual visit to the U.S. Congress. Lancelot had been born blind but could now clearly see the members of the Congress after receiving a revolutionary gene therapy treatment. A collaborative effort by teams of scientists and clinicians made history by showing that replacement of the damaged RPE65 gene with a healthy one could restore vision in animals.

Oleg Alekseev, MD, PhD joined Duke Eye Center faculty in 2022, helps translate proteasome enhancement into an effective treatment.

The concept of proteasome enhancement, to assist in clearing of damaged proteins in the retina, was discovered in the laboratory of Vadim Arshavsky, PhD. His laboratory reported promising treatment results in animals with the same mutations as those found in human patients.

The path to curing blindness in human patients was now in sight. The treatment entered clinical trials, and for the first time, children treated with a healthy replacement gene could see the faces of their parents and siblings. Upon completion of the trial, the drug, voretigene neparvovec-rzyl, known commercially as Luxturna® became the first gene therapy approved by the FDA to treat any blinding genetic condition. The landmark bench-to-bedside development of Luxturna® emphasized just how much science can do to improve the wellbeing of the public; but it also emphasized how many resources are required at every step from scientific discovery to clinical application.

Luxturna® Comes to Duke

Duke Eye Center is a premier destination for the treatment of vitreoretinal diseases, offering the latest in patient care. As a recently Certified Center of Excellence for Luxturna®, Duke is the only Luxturna® treatment center between Philadelphia and Miami for patients on the East Coast of the U.S. Patients eligible for Luxturna® treatment are cared for by a team of expert clinicians, including specialists in the diagnosis and management of inherited retinal diseases and vitreoretinal surgeons with advanced expertise in delivering gene therapy medications to the retina. The clinical team is supported by a dedicated genetic counselor working with patients and their families to uncover their diagnoses through specialized genetic testing. An important aspect of patient care is a comprehensive retinal electrophysiology facility, where patients undergo sophisticated testing, such as electroretinography (ERG), to measure the ability of the retina to detect light. This detailed testing gives the retina specialist information needed to identify candidates, prepare for and monitor treatment.

Beyond Current Therapy: The Quest for Universal Therapies

The development of Luxturna® is a monumental achievement, but this is just a first step in helping patients suffering from inherited retinal degenerations. Patients eligible for Luxturna® treatment represent less than one in a thousand of all people suffering from these conditions.

Inherited Retina Dystrophies

Maldonado, MD

Clinical Team

This is because there are more than 300 other genes whose defects lead to various forms of this disease, with more still discovered every year and only a handful addressed in ongoing trials. A major challenge with developing new therapies, especially gene therapy, is that it takes a tremendous amount of time and money to bring each treatment to clinic.

To overcome this challenge, scientists at Duke Eye Center are working to develop universal therapies that can save sight regardless of which genes are mutated. The scientific foundation of this pursuit is their discovery that many mutations causing inherited retinal degenerations lead to a buildup of damaged proteins in the retina. As everywhere else in the body, the retina has a built-in system for garbage disposal called proteasomes, which eliminate damaged proteins to keep the retina healthy. In retinas affected by inherited degenerations, proteasomes may be overwhelmed and become unable to keep up with the disposal of damaged proteins. A sound solution would be to bring new proteasomes to the rescue, and this is exactly what Duke scientists strive to bring to degenerating retinas in order to clear proteins damaged by disease-causing mutations.

The concept of proteasome enhancement was discovered in the laboratory of Vadim Arshavsky, PhD, a world-renowned retina scientist and Vice Chair for Basic Science Research at Duke Eye Center. His laboratory reported promising treatment results in animals with the same mutations as those found in human patients.

Much more remains to be done to translate this scientific discovery into an effective treatment. These efforts are spearheaded by Oleg Alekseev, MD, PhD who joined Duke Eye Center faculty in

Lejla Vajzovic, MD, FASRS

Surgical Team

Genetic Counselor

2022. Trained as both a scientist and a clinician, he is uniquely qualified to move this program forward. “Learning from my patients in the clinic inspires me to work tirelessly in the laboratory to better understand their conditions and to devise novel treatments to improve the quality of their lives”, said Alekseev.

Pioneering the Future of Vision at Duke

To integrate, facilitate and expand the audacious efforts of these and other researchers, Duke Eye Center has an exciting plan to establish the Center for Innovative Treatments of Retinal Degenerations. This will establish a robust translational research pipeline, whereby the ideas generated in laboratories and clinics will be converted into novel therapies. In this pipeline, new discoveries will be evaluated in blind animals first, followed by a streamlined process of developing and testing new therapeutics, and subsequently advancing the most promising candidates to clinical trials.

Other scientists at Duke Eye Center engaged in drug discovery and development to cure inherited blindness are Sidney Gospe, MD, PhD, who addresses rare but disastrous and currently incurable blinding conditions affecting the optic nerve, and Jeremy Kay, PhD, who is tackling a severe form of childhood blindness by using gene therapy.

Duke is fortunate to have a broad range of expertise on the same campus, which allows for enhanced collaboration. With the expertise in place, financial resources are needed to continue groundbreaking research that will hopefully one day cure blindness for people with inherited retinal degenerations. 05