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CHOP celebrates EC approval of first and only gene therapy for patients with inherited retinal disease

Reviewed by James Ives, MPsychDec 6 2018

Children's Hospital of Philadelphia (CHOP) celebrates a pivotal moment in medicine: approval by the European Commission (EC) of LUXTURNA® (voretigene neparvovec), the first and only gene therapy for patients with an inherited retinal disease, last month. This also makes LUXTURNA the first gene therapy for a genetic disease that has received regulatory approval in both the U.S. and European Union (EU).

The EC approved LUXTURNA, a one-time gene therapy for the treatment of vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations, in pediatric and adult patients who have sufficient viable retinal cells. RPE65 -mediated inherited retinal disease is a progressive condition that leads to total blindness in most patients.

The authorization is valid in all 28 member states of the EU, as well as Iceland, Liechtenstein and Norway. In December 2017, the U.S. Food and Drug Administration (FDA) approved LUXTURNA for use in patients in the U.S.

"The European Commission's approval of LUXTURNA highlights the vital role of pediatric research in developing breakthrough cures," said Bryan Wolf, MD, PhD, Chief Scientific Officer and Chair of the Department of Biomedical and Health Informatics at Children's Hospital of Philadelphia. "The research conducted as a collaborative effort between CHOP's Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT) and investigators at the Perelman School of Medicine at the University of Pennsylvania laid the groundwork for this revolutionary gene therapy, which was developed and is now manufactured by Spark Therapeutics. Today, we are thrilled to see LUXTURNA approved as a therapy for children and adults outside the U.S."

CHOP founded Spark Therapeutics in 2013 in an effort to accelerate the timeline for bringing new gene therapies to market. Spark's mission, to create a world where no life is limited by genetic disease, was to build on the foundational research conducted over a multi-year period by the CHOP and Penn Medicine teams.

Beginning in 2000, the initial research for LUXTURNA was conducted by Jean Bennett, MD, PhD, F.M. Kirby professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania's Scheie Eye Institute, and Albert M. Maguire, MD, a professor of Ophthalmology at Penn's Perelman School of Medicine and an attending physician at CHOP. Bennett and Maguire joined forces with then-CHOP researcher Katherine A. High, MD, a gene therapy pioneer who directed the CCMT and who is now Spark's President and head of research and development. Dr. Maguire served as a Principal Investigator of the therapy's clinical trials.

In the U.S., the gene therapy is currently administered at 10 treatment centers by leading retinal surgeons who receive training provided by Spark Therapeutics on the administration procedure.

In January 2018, Spark Therapeutics entered into a licensing and supply agreement with Novartis covering development, registration and commercialization rights to LUXTURNA in markets outside the U.S. Upon the transfer of the marketing authorization from Spark Therapeutics to Novartis. Novartis can commercialize LUXTURNA in the EU/EEA. Novartis already has exclusive rights to pursue development, registration and commercialization in all other countries outside the U.S., and Spark Therapeutics will supply the gene therapy to Novartis.






New drug treatment can override genetic fault that causes choroideremia

Dec 5 2016

Researchers with funding from Fight for Sight have demonstrated that a new drug treatment for cystic fibrosis and Duchenne muscular dystrophy can override a genetic fault that causes choroideremia – a severe blinding disorder. Treatment with Ataluren restored the function of rab escort protein 1 (REP1) – a protein that is critical for vision – in skin cells from a patient with choroideremia and in a zebrafish model.

Choroideremia is a rare inherited retinal dystrophy caused by any number of faults in the CHM gene which encodes instructions for making REP1. Around 1 in 3 of these faults are nonsense mutations - single letter substitutions that generate a premature instruction for cells to stop assembling the protein.

REP1 is important for cells throughout the body to process protein correctly, but is particularly active in the retina. The loss of function caused by nonsense mutations in CHM damages both the light-detecting photoreceptor cells of the retina and the blood vessel layer (choroid) that supplies them.

Ataluren (PTC Therapeutics) is designed to weaken the cell’s recognition of nonsense mutations. The drug allows cells to misread an abnormal stop instruction, permitting full-length protein to be made that functions normally.

Dr Mariya Moosajee at UCL Institute of Ophthalmology is first author on the study, which is published in Human Molecular Genetics. She said:

In this study we have used two independent models of choroideremia. Patient-derived skin cells with absent REP1 function as a model for testing pharmacological therapy with Ataluren and related compounds; and the zebrafish as the only nonsense mutation animal model of choroideremia, enabling study of the whole retina in response to treatment.
In the zebrafish model, Ataluren prevented the onset of retinal degeneration and significantly reduced oxidative stress and programmed cell death. REP1 production increased by 23% and its biological function was restored from 0% to 98%. Although we did not see a measurable increase in REP1 production in the patient-derived cells, biological function was restored from 0% to 42%, indicating that some quantity of healthy REP1 was produced.

Dr Dolores M Conroy is Fight for Sight’s Director of Research. She said:

These results show the potential for this class of drug to rescue retinal function in choroideremia and other inherited retinal dystrophies due to nonsense mutations. The most obvious potential is in the earlier stages when the retina is still functional and able to produce restored protein when treated.
Ataluren is orally administered and has a demonstrably good safety profile. It has already had some success in clinical trials for other nonsense mutation-based inherited disorders. This could provide an alternative treatment to gene replacement therapy for some choroideremia patients.





TSRI scientists discover how key protein establishes proper vision

Mar 6 2017

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered how a protein called α2δ4 establishes proper vision. Their research helps explain why mutations in the gene encoding α2δ4 lead to retinal dystrophy, a disease characterized by defective color vision and night blindness.

To study how this protein supports vision, the researchers modeled retinal dystrophy in mice. Like humans, mice lacking α2δ4 succumbed to the disease and their vision was compromised.

"Much of our work is driven by desire to understand what goes awry in a range of blinding conditions," explained TSRI Professor Kirill A. Martemyanov, senior author of the new study. "Now we have found a molecule that plays a key role in allowing photoreceptors to plug into the neural circuit and transmit the light signals they receive to the brain."

The study was published online recently in the journal Neuron.

A Secret Ingredient for Vision

Our vision depends on two types of photoreceptors in the light-sensitive layer of eye called the retina. Rods photoreceptors detect photons at the lowest levels of light and support night vision, and cone photoreceptors sense bright light and discriminate between colors. Both rods and cones must wire into a neural circuit of the retina to send information to the brain.

Martemyanov and his colleagues are studying the neural connections that make vision possible. In a previous study, the researchers identified a novel cell-adhesion protein called ELFN1 that rods use for making contacts with their partners, called bipolar neurons. However, how ELFN1 accomplishes the task of photoreceptor wiring was not clear.

In the new study, experiments spearheaded by TSRI Research Associate Yuchen Wang of the Martemyanov laboratory showed that this connectivity requires α2δ4 to join a structure, called a higher order macromolecular complex, with ELFN1 and other proteins called calcium channels. These calcium channels trigger the release of the chemical messenger glutamate, which photoreceptors use for communicating with bipolar neurons.

In short, Wang explained, without both α2δ4 and the other calcium channels in the macromolecular complex, rods cannot connect to the neural circuit. "We found that α2δ4 is essential for organizing the presynaptic compartment of rod photoreceptors," he said.

Strikingly, eliminating the corresponding gene for α2δ4 in a mouse model interrupted the transmission of light signals from photoreceptors to the brain without affecting the ability to detect light. "It's like you are trying to make a phone call--and your phone is fully functional--but you are not heard because there is no signal," Martemyanov said.

Cones seemed to handle the lack of α2δ4 only slightly better.

Without the α2δ4, mice failed to see under dim light conditions and could not navigate a maze in low light due to their dysfunctional rods. Their cones were affected too, but they could still send some weak signals through to the brain.

"Their dim-light vision was completely abolished," said Martemyanov. "And the signal from the cones could barely make it." Wang said the researchers are doing more research now to account for this difference between rods and cones.

A Potential Way to Keep Eyes Healthy

Going forward, Martemyanov and his team plan to study whether manipulating α2δ4 could help photoreceptors transmit their signals and maintain connectivity to stay functional longer in models of age-related vision loss, a major blinding condition in humans.

"If we can entice dying photoreceptors to augment their communication with the retina circuitry and preserve the connections they make, we can likely delay the loss of vision in degenerative conditions like age-related macular degeneration," Martemyanov said.

The researchers also think that wiring factors such as α2δ4 and ELFN1 could also help researchers address a current challenge in using stem cells to correct vision loss.

Martemyanov explained that current efforts of many laboratories are currently directed towards replacing dead photoreceptor cells with stem cell-derived rods and cones as a strategy to restore vision; however, integrating the new photoreceptors into the retina circuit has been a challenge. The new study suggests that α2δ4 may be the secret ingredient for getting these new cells to properly wire into the neural circuit.





Study shows children with rare eye disease have greatest benefit from gene therapy

Apr 18 2016

Scientists at Oregon Health & Science University's Casey Eye Institute and Baylor College of Medicine's Cullen Eye Institute published findings from a two-year Phase I clinical trial in the journal Ophthalmology, which showed that children had the greatest benefit from gene therapy for treatment of Leber congenital amaurosis (LCA) or severe early childhood onset retinal degeneration (SECORD). Importantly, 9 of the 12 participants experienced improvement in visual function. LCA and SECORD are related inherited retinal degenerative diseases that cause severe loss of vision in infancy due to mutations in the gene RPE65.

"While other studies have shown similar results, an important finding from this study is that the young patients saw the greatest benefit in treatment. In addition, this study for the first time demonstrates improvement in visual field by using visual field modeling and assessment," said Timothy Stout, M. D., Ph.D., M.B.A., a senior author and study surgeon who previously worked at OHSU Casey Eye Institute and is now director of the Baylor Cullen Eye Institute.

The study included 8 adults and 4 children ages 6 to 39, and showed that treatment for LCA and SECORD delivered by subretinal injection in the poorer-seeing eye, was safe, the primary outcome for Phase I clinical trials. Nine out of 12 patients experienced an improvement in visual acuity (sharpness of vision) or an improvement in visual field.

In order to more accurately measure visual field, the total area in which objects can be seen (both central and side vision), Richard Weleber, M.D. of OHSU's Casey Eye Institute, senior author and professor of ophthalmology in the OHSU School of Medicine, Casey Eye Institute developed a novel quantitative visual field analytic tool, called Visual Field Modeling and Assessment.

"I am very optimistic about these study findings," said Weleber. "Gene replacement therapy has proven to be the most promising method to halt progression of childhood blindness due to single gene defects. The eye is a perfect platform for gene therapy because we can treat one eye to see how it responds compared to the other eye."

Gene therapy is a new approach to treating rare genetic diseases and has shown a lot of promise in treating rare genetic eye diseases such as LCA due to mutations of the RPE65 gene. For this study, surgeons used a viral vector to insert a normal copy of the mutated gene (RPE65) into the retinal cells of the patient's eye to restore retinal function.

OHSU Casey Eye Institute's gene therapy program is world-renowned, with leading experts currently overseeing five gene therapy trials, the most retinal gene therapy clinical trials being conducted at a single institution. Patients travel from all over the world to participate in these groundbreaking studies targeting severe inherited blinding disorders.

"Treatments for childhood blindness have profound effects because these children have their whole lives ahead of them," said David Wilson, M.D., director of the OHSU Casey Eye Institute, chair of the Department of Ophthalmology in the OHSU School of Medicine and study co-author. "Demonstrating the effectiveness of gene therapy in the eye will have broad implications for the rest of medicine as well."


Oregon Health & Science University