It was reported that Patients suffering from a rare congenital disease that leaves them nearly blind showed as much as 100-fold improvement after undergoing gene therapy aimed to fix genetic defect said to be involved in causing the condition. The study authors reported patients showed an extraordinary 10,000-fold improvement in vision after receiving the highest dose of the gene therapy. According to the study participants from University of Pennsylvania’s Perelman School of Medicine.
Their findings were published in the journal The Lancet.
That 10,000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,
One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.
Artur Cideciyan, PhD
A Phase 1/2 trial included 15 individuals in total, among them three pediatric patients. The patients all suffered from the disease Leber congenital amaurosis caused by a gene that is essential in making proteins crucial to vision. LCA stands for less than 100,000 people and causes a lot of vision loss mainly from infancy.
All subjects had severe loss of vision with their best measure of vision being equal or worse than 20/80-that is, if a typically sighted person could see an object clearly at 80 feet, these patients would need to move up to at least 20 feet to see it. For individuals, eyeglasses can be of little help because they only correct deficiencies in the ability of an eye to focus light, and not causes of vision medically, such as genetic diseases of the retina like LCA1.
This gene therapy product, ATSN-101, derived from the AAV5 microorganism, was used in the clinical trial to test doses delivered by a surgical injection under the retina. The first part of this study divided cohorts of three adults each into three different dose levels: low, medium, or high. Evaluations were to be carried out at each dose level for safety and acceptability before dose escalation for each successive cohort. The single-arm, open-label part of the trial involved an advanced dose given in an adult cohort of three and a pediatric cohort of three participants after successive cohorts’ safety evaluations.
Improvements were visible as early as the first month after treatment and remained stable for at least 12 months. The treated patients are continuing to be followed. Of the six patients given high doses, three were able to complete a mobility course in various light settings with the highest score possible. Other tests used eye charts or measured the dimmest light stimuli visible to the patients in a darkened room.
Two of the nine patients who were given the highest dosage saw a 10,000-fold increase in eyesight.
Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,
It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.
Artur Cideciyan, PhD
First, it was a study trying to establish how safe the gene therapy and its different dosage levels were. They did find that a number of patients showed some side effects, but the overwhelming majority had to do with the surgical procedure per se. The most common one was conjunctival hemorrhage-the breaking of small blood vessels underneath the clear surface of the eye-which healed. Only two patients improved their ocular inflammation once it was treated with corticosteroids. No relevant drug-related adverse effects were observed with the study medication.
This follows another successful ophthalmologic trial by Penn in this case, restoring the sight of patients with a different form of LCA. Earlier in 2024, several patients with the form of LCA associated with mutations of the CEP290 gene had their sight improved thanks to the CRISPR-Cas9 gene editing. That study co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, the Irene Heinz-Given and John LaPorte Research Professor in Ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations used similar tests on the children of any gene editing work.
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The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,
The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.
Tomas S. Aleman, MD
Whereas advancement of this investigative drug into the clinics would necessitate a second trial, participants of whom would be randomly assigned to treatment doses, neither the patients nor the investigators of the trial would know what each is getting, thereby avoiding possible biases in results.
Source: Penn Medicine News
Journal Reference: Yang, Paul et al. “Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.” Lancet (London, England) vol. 404,10456 (2024): 962-970. DOI: 10.1016/S0140-6736(24)01447-8.
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