Synthetic viral vector and surgical approach enable efficient gene transfer into primate inner ear

A synthetic viral vector and a new surgical approach developed at Mass Eye and Ear has enabled efficient gene transfer into the inner ear of non-human primates, a research team working to develop effective treatments for hearing loss and hearing loss has reported. vestibular disorders.

In previous studies, the Mass Eye and Ear research team has demonstrated the ability to successfully target the inner ear and show therapeutic efficacy in mouse models. The new findings, published March 15 in Nature Communicationsuggest that an adeno-associated virus (AAV) vector called Anc80L65 can be combined with a new surgical approach, consisting of a transmastoid posterior tympanotomy, to deliver genes into the inner ear, which could provide a promising route to translate this research in humans.

Hearing impairment affects millions of individuals and impairs their ability to communicate, yet virtually no drug treatment is available to alleviate these conditions. Delivery to the cochlea is one of the biggest challenges. Here, we show the potential for a one-time surgery of a sustainable gene-based drug platform to eventually change the status quo for patients. »

Luk Vandenberghe, PhD, co-author of the study, director of the Grousbeck Gene Therapy Center at Mass Eye and Ear and associate professor of ophthalmology at Harvard Medical School

Hearing loss, a global epidemic that remains untreated

Hearing loss affects more than 400 million people worldwide. The most common type of hearing loss is called sensorineural hearing loss, which usually stems from damage to the delicate structures of the inner ear and the destruction of the hair cells responsible for hearing. More than half of all cases of childhood deafness are genetic and caused by mutations in over 120 different genes, fueling the need for a gene therapy solution. Vestibular or balance disorders can also originate in the inner ear and can be treated with such an approach.

In an effort to reach the inner ear, researchers have developed a surgical method to gently access what is called the round window membrane, which is an opening from the middle ear into the inner ear. Once inside the inner ear, gene therapy is delivered via a viral vector. This approach was inspired by cochlear implant surgery, which also requires access to the inner ear.

The new surgical method was developed by Konstantina Stankovic, MD, PhD, Bertarelli Foundation Professor and Chair of the Department of Otorhinolaryngology-Head and Neck Surgery at Stanford University School of Medicine. and Michael McKenna, MD, co-founder and chief medical officer of Akouos. Both are former heads of the Otology and Neurotology Division at Mass Eye and Ear and faculty members at Harvard Medical School, where they developed this surgical method.

The vector that transfers gene therapy to the inner ear is called Anc80L65, which is an AAV first created in Dr. Vandenberghe’s lab and previously shown in mouse studies to be a potent transfer vector of gene to several organs.

Efficient and feasible gene transfer to the inner ear

The inner ear is a blank space with many complex structures, which means invasive surgeries should be kept to a minimum. Gene therapy is beneficial since it is a one-time treatment that requires surgery.

The AAV surgical approach is comparable to what is used in approved and experimental gene therapies at Mass Eye and Ear for the treatment of disorders of the retina of the eye. During these therapies, surgery takes place before gene therapy is injected into the eye.

In the new study, the researchers tested the effectiveness of two AAV technologies – AAV1, a vector established for use in the cochlea, and the synthetic Anc80L65 – targeting inner hair cells, the main sound sensors in the ear . The surgical and molecular aspects of delivery to the inner ear have been shown to be safe and well tolerated, which the authors say opens the door to future human applications. Anc80L65 in two animals transduced up to 90% of inner hair cells; AAV1 was significantly less effective at the same dose. AAV neutralizing antibodies were detected in serum but not in cerebrospinal fluid after injection in all animals, indicating that the gene therapy went to its target.

Results reveal that Anc80L65 can be delivered to the inner ear and consistently transduce cochlear and vestibular cells of young non-human primates using an optimized surgical approach that allows visualization of the round window prior to therapy injection. gene.

“Hearing loss is the most common sensory deficit in the world, and at least half of congenital hearing loss is attributable to genetic causes. So the potential for gene therapy is transformative,” said Dr. Stankovic. “This research demonstrates the feasibility of using a genetic and surgical approach to target specific cells in the inner ear of non-human primates. If it translates into effective therapies for humans, the impact will be enormous, similar to the how gene therapy has improved other disorders such as blindness.”

Developing treatments for incurable diseases

Studies that use this surgical approach and AAV to test gene therapies are underway for some of the specific genes leading to hearing loss in animal models, with hopes of one day translating this research into treatments for humans. . Technology is being explored not only to add genes, but also to remove genes that are toxic to hair cells.

“This research paves the way for translating this approach into humans and was a very necessary step that needed to be tested and elaborated,” said Dr. McKenna. “We are now using this approach routinely in experiments that test new treatments for inner ear disorders, such as hearing loss, and I hope to test this approach in clinical trials in the future.”


Journal reference:

Andrés-Mateos, E., et al. (2022) Choice of vector and surgical approach enables efficient cochlear gene transfer in the non-human primate. Communication Nature.

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