Children’s hospital of Philadelphia performed a gene therapy procedure to treat genetic hearing loss thanks to a technique developed in Italy. In this photograph, the patient with his family and the hospital's team. Credit: Children’s Hospital of Philadelphia (CHOP).
A gene therapy technique developed by an Italian team has allowed an 11-year-old boy with a rare form of congenital deafness to hear for the first time. The world-first result was achieved by a team at Children’s Hospital of Philadelphia, in the United States, and builds on the work of Alberto Auricchio's team at TIGEM Telethon Institute of Genetics and Medicine in Pozzuoli.
The boy’s condition is caused by defects in the OTOF gene, which codes for otoferlin, one among more than 150 genes known to cause deafness in humans. In principle, gene therapy can be used to replace the defective gene with a functioning one. Usually, a small viral vector such as adeno-associated virus (AAV) is used to carry genes, but a large gene such as OTOF is too heavy for the virus, which cannot carry long DNA sequences. “We could have used viral vectors with larger capacity than AAV, like lentiviruses (LV), but they are typically less efficient for in vivo gene therapy,” explains Auricchio.
The researchers in Naples came up with the idea of splitting the gene in two parts, each capable of fitting on a single viral vector and have them reassemble inside the patient’s cells. The scientists also incorporated the vectors with some recombinant gene sequences that guide the joining of the two halves, and splicing signals that help remove the extraneous sequences afterward. The method could ensure the desired protein is synthesized in the patient’s body.
Auricchio’s team has been working on new systems for gene therapy for 10 years, but had mostly focused on the treatment of rare eye diseases. “We work on Usher syndrome type 1b, that causes retinitis pigmentosa,” says Auricchio. Patients with this condition are deaf and blind from birth, he explains, and there is currently no treatment available. “For retinitis, we expect to enter clinical trials at the University hospital in Naples within a few months, after getting approval from the Italian drug agency”. The group is also working on Stargardt’s disease, the most common form of hereditary macular dystrophy.
While looking for funding for the retinitis pigmentosa trial — which has now been granted by the Sofinnova investment fund and the Telethon Foundation — Auricchio's team had licensed the technology to the American company Akous, a biotech company owned by Ely Lilly. That company then partnered with John Germiller’s team at the Children’s hospital in Philadelphia to experiment with gene therapy for deafness.
Last October, they performed surgery on the 11-year-old to deliver a gene therapy based on Auricchio’s system into his inner ear by an endoscope. After four months, the team reports, the boy has gone from complete deafness to a mild hearing loss and can hear voices and ambient sounds. A larger clinical trial in different hospitals is ongoing.
“We are very proud to see that our technology, originally designed for retinal diseases, has also contributed to develop an experimental therapy for deafness,” says Auricchio.
