adeno-associated virus (AAV)

This extraordinary development from Sweden’s Karolinska Institutet was announced in a July 3, 2025 news item on ScienceDaily, Note: This treatment was designed for a very specific type of genetically based deafness,

Gene therapy can improve hearing in children and adults with congenital deafness or severe hearing impairment, a new study involving researchers at Karolinska Institutet reports. Hearing improved in all ten patients, and the treatment was well-tolerated. The study was conducted in collaboration with hospitals and universities in China and is published in the journal Nature Medicine.

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The study comprised ten patients between the ages of 1 and 24 at five hospitals in China, all of whom had a genetic form of deafness or severe hearing impairment caused by mutations in a gene called OTOF. These mutations cause a deficiency of the protein otoferlin, which plays a critical part in transmitting auditory signals from the ear to the brain.

Effect within a month

The gene therapy involved using a synthetic adeno-associated virus (AAV) to deliver a functional version of the OTOF gene to the inner ear via a single injection through a membrane at the base of the cochlea called the round window.

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Best results in children

The younger patients, especially those between the ages of five and eight, responded best to the treatment. One of the participants, a seven-year-old girl, quickly recovered almost all her hearing and was able to hold daily conversations with her mother four months afterwards. However, the therapy also proved effective in adults.

“Smaller studies in China have previously shown positive results in children, but this is the first time that the method has been tested in teenagers and adults, too,” says Dr Duan. “Hearing was greatly improved in many of the participants, which can have a profound effect on their life quality. We will now be following these patients to see how lasting the effect is.”

No serious adverse reactions

The results also show that the treatment was safe and well-tolerated. The most common adverse reaction was a reduction in the number of neutrophils, a type of white blood cell. No serious adverse reactions were reported in the follow-up period of 6 to 12 months.

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A July 2, 2025 essay for The Conversation by Maoli Duan, one of the study’s authors, associate professor, and senior consultant at the Karolinska Institutet, provides more detail and context for the work, Note: Links have been removed,

Up to three in every 1,000 newborns has hearing loss in one or both ears. While cochlear implants offer remarkable hope for these children, it requires invasive surgery. These implants also cannot fully replicate the nuance of natural hearing.

But recent research my colleagues and I conducted has shown that a form of gene therapy can successfully restore hearing in toddlers and young adults born with congenital deafness.

Our research focused specifically on toddlers and young adults born with OTOF-related deafness. This condition is caused by mutations in the OTOF gene that produces the otoferlin protein –a protein critical for hearing.

The protein transmits auditory signals from the inner ear to the brain. When this gene is mutated, that transmission breaks down leading to profound hearing loss from birth.

Unlike other types of genetic deafness, people with OTOF mutations have healthy hearing structures in their inner ear – the problem is simply that one crucial gene isn’t working properly. This makes it an ideal candidate for gene therapy: if you can fix the faulty gene, the existing healthy structures should be able to restore hearing.

In our study, we used a modified virus as a delivery system to carry a working copy of the OTOF gene directly into the inner ear’s hearing cells. The virus acts like a molecular courier, delivering the genetic fix exactly where it’s needed.

The modified viruses do this by first attaching themselves to the hair cell’s surface, then convincing the cell to swallow them whole. Once inside, they hitch a ride on the cell’s natural transport system all the way to its control centre (the nucleus). There, they finally release the genetic instructions for otoferlin to the auditory neurons.

Our team had previously conducted studies in primates and young children (five- and eight-year-olds) which confirmed the virus therapy was safe. We were also able to illustrate the therapy’s potential to restore hearing – sometimes to near-normal levels.

But key questions had remained about whether the therapy could work in older patients – and what age is optimal for patients to receive the treatment.

To answer these questions, we expanded our clinical trial across five hospitals, enrolling ten participants aged one to 24 years. All were diagnosed with OTOF-related deafness. The virus therapy was injected into the inner ears of each participant.

We closely monitored safety during the 12-months of the study through ear examinations and blood tests. Hearing improvements were measured using both objective brainstem response tests and behavioural hearing assessments.

From the brainstem response tests, patients heard rapid clicking sounds or short beeps of different pitches while sensors measured the brain’s automatic electrical response. In another test, patients heard constant, steady tones at different pitches while a computer analysed brainwaves to see if they automatically followed the rhythm of these sounds.

For the behavioural hearing assessment, patients wore headphones and listened to faint beeps at different pitches. They pressed a button or raised their hand each time they heard a beep – no matter how faint.

Hearing improvements were both rapid and significant – especially in younger participants. Within the first month of treatment, the average total hearing improvement reached 62% on the objective brainstem response tests and 78% on the behavioural hearing assessments. Two participants achieved near-normal speech perception. The parent of one seven-year-old participant said her child could hear sounds just three days after treatment.

Over the 12-month study period, ten patients experienced very mild to moderate side-effects. The most common adverse effect was a decrease in white blood cells. Crucially, no serious adverse events were observed. This confirmed the favourable safety profile of this virus-based gene therapy.

Treating genetic deafness

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If you have time, Duan’s July 2, 2025 essay provides a few more details about the work and the researchers’ future plans.

Here’s a link to and a citation for the paper,

AAV gene therapy for autosomal recessive deafness 9: a single-arm trial by Jieyu Qi, Liyan Zhang, Ling Lu, Fangzhi Tan, Cheng Cheng, Yicheng Lu, Wenxiu Dong, Yinyi Zhou, Xiaolong Fu, Lulu Jiang, Chang Tan, Shanzhong Zhang, Sijie Sun, Huaien Song, Maoli Duan, Dingjun Zha, Yu Sun, Xia Gao, Lei Xu, Fan-Gang Zeng & Renjie Chai. Nature Medicine (2025) DOIhttps://doi.org/10.1038/s41591-025-03773-w: Published: 02 July 2025

This paper is behind a paywall.

Years ago I worked as a publicist for the BC (British Columbia) Motorcycle Federation’s Ride for Sight; they were raising funds for research into retinitis pigmentosa (RP). I hadn’t thought about that in years but it all came back when I saw this April 21, 2017 news item on ScienceDaily,

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego [UCSD] School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa.

Caption: This is a confocal micrograph of mouse retina depicting optic fiber layer. Credit: Image courtesy of National Center for Microscopy and Imaging Research, UC San Diego.

An April 21, 2017 UCSD news release by Scott LaFee (also on EurekAlert), which originated the news item, delves further into retinitis pigmentosa and this CRISPR research,

Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes’ photoreceptors, specialized cells in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells.

In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness.

In their published research, a team led by senior author Kang Zhang, MD, PhD, chief of ophthalmic genetics, founding director of the Institute for Genomic Medicine and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine, used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3.

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, allows researchers to target specific stretches of genetic code and edit DNA at precise locations, modifying select gene functions. Deactivating either Nrl or Nr2e3 reprogrammed rod cells to become cone cells.

“Cone cells are less vulnerable to the genetic mutations that cause RP,” said Zhang. “Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision.”

The scientists tested their approach in two different mouse models of RP. In both cases, they found an abundance of reprogrammed cone cells and preserved cellular architecture in the retinas. Electroretinography testing of rod and cone receptors in live mice show improved function.

Zhang said a recent independent study led by Zhijian Wu, PhD, at National Eye Institute, part of the National Institutes of Health, also reached similar conclusions.

The researchers used adeno-associated virus (AAV) to perform the gene therapy, which they said should help advance their work to human clinical trials quicker. “AAV is a common cold virus and has been used in many successful gene therapy treatments with a relatively good safely profile,” said Zhang. “Human clinical trials could be planned soon after completion of preclinical study. There is no treatment for RP so the need is great and pressing. In addition, our approach of reprogramming mutation-sensitive cells to mutation-resistant cells may have broader application to other human diseases, including cancer.”

Here’s a link to and a citation for the paper,

Gene and mutation independent therapy via CRISPR-Cas9 mediated cellular reprogramming in rod photoreceptors by Jie Zhu, Chang Ming, Xin Fu, Yaou Duan, Duc Anh Hoang, Jeffrey Rutgard, Runze Zhang, Wenqiu Wang, Rui Hou, Daniel Zhang, Edward Zhang, Charlotte Zhang, Xiaoke Hao, Wenjun Xiong, and Kang Zhang. Cell Research advance online publication 21 April 2017; doi: 10.1038/cr.2017.57

This paper (it’s in the form of a letter to the editor) is open access.

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Tag Archives: adeno-associated virus (AAV)

Using CRISPR to reverse retinosa pigmentosa (eye disease)