A Penn Medicine patient with a genetic form of childhood blindness gained vision, which lasted more than a year, after receiving a single injection of an experimental RNA therapy into the eye. Visual function at the eye’s foveal cone photoreceptors improved slowly, reaching a substantial peak near three months after the injection.
Graphic courtesy of Artur V. Cideciyan created with BioRender.com.
Penn Medicine researchers have found that a mutation-specific RNA therapy improved vision with lasting effects
A Penn Medicine patient with a genetic form of childhood blindness gained vision, which lasted more than a year, after receiving a single injection of an experimental RNA therapy into the eye. The clinical trial was conducted by researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania. Results of the case, detailed in a paper published today in Nature Medicine, show that the treatment led to marked changes at the fovea, the most important locus of human central vision.
The treatment was designed for patients diagnosed with Leber congenital amaurosis (LCA) — an eye disorder that primarily affects the retina — who have a CEP290 mutation, which is one of the more commonly implicated genes in patients with the disease. Patients with this form of LCA suffer from severe visual impairment, typically beginning in infancy.
“Our results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations,” said co-lead author Artur V. Cideciyan, PhD, a research professor of Ophthalmology. “Importantly, we established a comparator for currently-ongoing gene editing therapies for the same disease, which will allow comparison of the relative merits of two different interventions.”
In an international clinical trial led at Penn Medicine by Cideciyan and Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology, participants received an intraocular injection of an antisense oligonucleotide called sepofarsen. This short RNA molecule works by increasing normal CEP290 protein levels in the eye’s photoreceptors and improving retinal function under day vision conditions.
In a 2019 study published in Nature Medicine, Cideciyan, Jacobson, and collaborators found that injections of sepofarsen repeated every three months resulted in continued vision gains in 10 patients. The eleventh patient, whose treatment was detailed in the latest Nature Medicine paper, received only one injection and was examined over a 15-month period. Prior to treatment, the patient had reduced visual acuity, small visual fields, and no night vision. After the initial dose, the patient decided to forgo the quarterly maintenance doses, because the regular dosing could lead to cataracts.
After a single injection of sepofarsen, more than a dozen measurements of visual function and retinal structure showed large improvements supporting a biological effect from the treatment. A key finding from the case was that this biological effect was relatively slow in uptake. The researchers saw vision improvement after one month, but the patient’s vision reached a peak effect after month two. Most striking, the improvements remained when tested over 15 months after the first and only injection.
According to the researchers, the extended durability of vision improvement was unexpected and provides implications for treating other ciliopathies — the name of the large category of diseases associated with genetic mutations encoding defective proteins, which results in the abnormal function of cilia, a protruding sensory organelle found on cells.
“This work represents a really exciting direction for RNA antisense therapy. It’s been 30 years since there were new drugs using RNA antisense oligonucleotides, even though everybody realized that there was great promise for these treatments,” said Jacobson. “The unexpected stability of the ciliary transition zone noted in the patient prompts reconsideration of dosing schedules for sepofarsen, as well as other cilium-targeted therapies.”
One reason why antisense oligonucleotide has proven successful in treating this rare disease, according to the researchers, is that these tiny RNA molecules are small enough to get into the cell nucleus, but are not cleared very quickly, so they remain long enough to do their work.
“There are now, at least in the eye field, a series of clinical trials using antisense oligonucleotides for different genetic defects spawned by the success of the work in CEP290-associated LCA from Drs. Cideciyan and Jacobson,” said Joan O’Brien, MD, chair of Ophthalmology in the Perelman School of Medicine and director of the Scheie Eye Institute
For future studies, the Penn authors are planning gene-specific therapies for other currently incurable blinding inherited retinal disorders.
The Latest Updates from Bing News & Google News
Go deeper with Bing News on:
- Centenary Institute supports NSW RNA pushon August 23, 2021 at 6:14 pm
The Centenary Institute is pleased to note its involvement in, and support of, the newly announced NSW RNA Production and Research Network involving ...
- Genevant scores with Takeda again as LNPs continue to attract interest for RNA therapyon August 23, 2021 at 7:41 am
Barely five months after signing on to a $600 million deal with Takeda, Genevant has returned to ink another big biobuck tie-up with its new collaborators. The Canadian and Swiss biotech, spawned out ...
- Genevant pens $303M biobucks pact with Takeda, aiming at rare liver diseases using gene therapyon August 23, 2021 at 4:55 am
Forever biotech friend Takeda is signing up to a new deal with Genevant as it doubles down on the company. Back in March, the pair signed a deal worth $600 million in an upfront/biobucks mix to tap ...
- New UNSW institute to spearhead NSW government drive for RNA researchon August 22, 2021 at 3:22 pm
UNSW Sydney will lead a new institute which will aim to establish an RNA-based manufacturing hub in Sydney following the NSW Government’s call to drive RNA production in the State.The high-speed devel ...
- RNA is the future. So... what can you do with it?on August 20, 2021 at 7:31 pm
To tell the story of RNA we need to go back to dawn of life on Earth. Long before DNA (deoxyribonucleic acid) showed up to steal the limelight, it was RNA (ribonucleic acid) that acted as the genetic ...
Go deeper with Google Headlines on:
Go deeper with Bing News on:
- Acta biomaterialiaon August 17, 2021 at 5:00 pm
The Construction of Retinal Pigment Epithelium Sheets with Enhanced Characteristics and Cilium Assembly Using iPS Conditioned Medium and Small Incision Lenticule Extraction Derived Lenticules.
- Ultrastructural Characterization of Primary Cilia in Pathologically Characterized Human Glioblastoma Multiforme (GBM) Tumorson July 17, 2021 at 5:00 pm
Similarly, ultrastructural examination revealed a normal basal body with a fully formed mature primary cilium, consistent with normal morphology (Figure 2 compared to Figure 1). The cilium-pit was ...
- SKI: Timeline of Progresson December 26, 2018 at 1:41 am
A drug targeting this process (Xofluza) was approved in 2018 as a treatment for the flu ... different parts of the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways with targeted drugs leads to feedback ...
- Engineering Discovery: the Story of SKIon August 18, 2018 at 12:26 am
The first chemotherapy drugs, the first immune-based treatments for cancer, and a variety of targeted therapies all had their origins at ... depends on a cell structure called the primary cilium for ...
- Autosomal Dominant Polycystic Kidney Diseaseon February 17, 2017 at 1:34 am
Guay-Woodford LM: Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome complex ... Diagnosis, pathogenesis, and treatment prospects in cystic kidney disease.