La terapia génica puede restaurar la visión nocturna después de décadas de ceguera congénita

Los pacientes tenían la enfermedad congénita de Leber, un tipo de ceguera congénita hereditaria.

Según investigadores del Scheie Eye Institute de la Perelman School of Medicine en Universidad de PennsylvaniaLos adultos con una forma genética de ceguera infantil experimentaron una recuperación significativa de la visión nocturna a los pocos días de recibir la terapia génica experimental.

Los pacientes tenían amaurosis congénita de Leber (LCA), que es la ceguera congénita causada por mutaciones en el gen GUCY2D. Los resultados fueron publicados en la revista iCiencia. Los investigadores administraron la terapia génica AAV, que contiene[{» attribute=»»>DNA of the healthy form of the gene, into the retina of one eye for each of the patients in line with the clinical trial protocol. Each patient had significant gains in rod-type photoreceptor cell-mediated visual functions in the treated eye within days after treatment. The majority of the human eye’s ability to see in low light comes from rod cells, which are very light-sensitive.

“These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness,” said study lead author Samuel G. Jacobson, MD, Ph.D., a professor of Ophthalmology at Penn.

One in every 40,000 newborns is born with LCA, which is one of the most frequent congenital blindness conditions. While the extent of vision loss might vary from patient to patient with LCA, all such individuals experience substantial visual impairment starting in the first few months of life. There are more than two dozen genes whose dysfunction can cause LCA.

Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the “phototransduction cascade”—the process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients’ light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as “can [now] Haz cosas y personas en la oscuridad».

Lo sorprendente fue la rápida mejoría después del tratamiento. En ocho días, ambos pacientes ya mostraron una eficacia medible”, dijo el coautor del estudio, Artur V.

Para los investigadores, los resultados confirman que la terapia génica GUCY2D restaura la función de los fotorreceptores basados ​​en bastoncillos y sugieren que los pacientes con GUCY2D-LCA con disfunción grave del pene probablemente se beneficien significativamente del tratamiento. El mensaje práctico es que debe haber un enfoque en las mediciones de la visión del pene cuando se examinan los candidatos a LCA y al monitorearlos a lo largo de la prueba de tratamiento.

Los hallazgos también subrayan el hecho notable de que en algunos pacientes con pérdida de visión congénita severa, las redes de células de la retina que median la visión permanecen en gran parte vivas e intactas, y solo necesitan reabastecerse de la proteína perdida para comenzar a funcionar nuevamente, dijeron los investigadores. o menos inmediatamente.

Referencia: «Restauración de la visión nocturna en días posteriores a décadas de ceguera congénita» por Samuel J. Jacobson, Artur F. Sidisian, Allen C. Ho, Alejandro G. Roman, Vivian Wu, Alexandra V. Garavalo, Alexander Somaruca y Aaron K. Krishnan, Malgorzata Swider, Abraham A. Mascio, Christine N. Kay, Dan Yoon, Kenji P. Fujita, Sanford L. Boye, Igor V. Peshenko, Alexander M. Dizhoor y Shannon E. Boye, 3 de octubre de 2022, iCiencia.
DOI: 10.1016 / j.isci.2022.105274

El ensayo clínico en curso se registró en Clinicaltrials.gov como ensayo NCT03920007.

El estudio fue financiado por Atsena Therapeutics, Inc. , desarrollador de la terapia génica GUCY2D. Institutos Nacionales de Salud; Es del Departamento de Salud de Pensilvania.