Gene therapy trial launched for X-linked retinitis pigmentosa


Researchers have injected their first patient with a virus engineered to remodel the gene responsible for X-linked retinitis pigmentosa (XLRP).

Researchers have injected their first patient with a virus engineered to remodel the gene responsible for X-linked retinitis pigmentosa (XLRP).

“If successful, this gene therapy has the potential to transform the lives of many patients,” said David Fellows, chief executive officer, Nightstar, a gene therapy company in Oxford, according to an Oxford University press release.

The injection took place as part of a multicenter open-label study designed to enrolat least 24 male patients in a 12-month trial of safety and tolerability. It is the first in the world to test a treatment for retinitis pigmentosa caused by the retinitis pigmentosa GTPase regulator (RPGR) gene, the press release said.

One of the leading causes of blindness in young people, retinitis pigmentosa is currently untreatable and leads to a slow and irreversible loss of vision due to the loss of rods and cones.

The most prevalent form of XLRP is caused by mutations in the RPGR gene, accounting for over 70% of XLRP patients.

Half of the RPGR gene has only 2 letters, A and G, instead of the GTAC combination found in most other genes, said Dr Robert MacLaren, University of Oxford, who is working with Dr. Fellows on the project. “This makes the gene very unstable and prone to mutations.”

It also poses a particular challenge for researchers seeking to repair the defective copies of the gene found in people with the disease, he said.

Using a viral vector known as adeno-associated virus (AAV), Dr MacLaren and colleagues delivered a codon-optimised copy of the RPGR gene into cells of the patient’s eye.

“Based on previous findings in preclinical in vivo disease models, which have shown significant rescue of photoreceptors, we believe this approach has great potential to restore or maintain sight in patients,” said Dr MacLaren in a Nightstar press release. “The unique codon-optimisation strategy overcomes the inherent instability problems of RPGR that confounded earlier attempts at gene replacement.”

The operation took place at the Oxford Eye Hospital, part of the Oxford University Hospitals National Health Service (NHS) Foundation Trust.

According to the procedure described on the Nightstar website, surgeons detach the patient’s retina from the underlying retinal pigment epithelium. Then, they inject about 0.1 mm of fluid containing vector genome particles into the sub-retinal space.

Preliminary results


Nightstar is a biopharmaceutical spinout company of Oxford developing gene therapies for multiple inherited retinal diseases.

It has already reported promising preliminary results on a retinal gene therapy for choroideremia, an X-linked genetic disease that causes blindness in about 1 in 50,000 people.

Choroidermia results from mutations in the CHM gene. In the results reported in 2014 in the Lancet, researchers administered 0.6–1.0×1010 genome particles in 1 eye each of 6 male patients aged 35-63 years.

Despite undergoing retinal detachment, 2 patients with advanced choroideremia and low baseline best corrected visual acuity (BCVA) experienced significant improvement over 6 months. One gained 21 letters and the other gained 11 letters. The other 4 patients with near normal BCVA at baseline recovered to within 1 to 3 letters.

The mean gain in visual acuity was 3.8 letters. Maximal light sensitivity measured with dark-adapted microperimetry increased from 23.0 dB at baseline to 25.3 dB in the treated eye.

The mean increase in retinal sensitivity in the treated eyes correlated with the vector dose administered per square millimetre of surviving retina.

Meanwhile, small non-significant reductions were noted in the control eyes in both maximal and mean sensitivity.

More than 40 patients with choroideremia have received doses of AAV to date, according to the Nightstar website. Researchers have now followed the 6 patients for followed for 5 years, and they will have 2 years of data on another cohort this year.

The company “expected to enter phase III pivotal testing, pending final discussions with the United States Food and Drug Administration [FDA],” according to the company’s website.

Similar clinical trials of AAV as a treatment for choroideremia are underway at the University of Miami, Miami and the University of Pennsylvania, Philadelphia, both in the United States; and at the University of Alberta, Edmonton, Canada.

Nightstar anticipates beginning a phase I/II clinical trial of gene therapy for macular dystrophy in late 2018.

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