Tag Archives: #hearingloss

Researchers Pinpoint Possible Way to Prevent Permanent Hearing Loss Caused by Common Childhood Cancer Drug (Medicine)

Deeper understanding of how the chemotherapy drug cisplatin works in the body may potentially eliminate the toxic side-effect in childhood cancer survivors.

University of Alberta scientists have identified a receptor in cells that could be key to preventing permanent hearing loss in childhood cancer survivors who are being treated with the drug cisplatin. The researchers believe by inhibiting the receptor, they may be able to eliminate toxic side-effects from the drug that cause the hearing loss.

Cisplatin is an incredibly effective chemotherapeutic when it comes to treating solid tumours in children, contributing to an 80 per cent overall survival rate over five years, according to U of A researcher Amit Bhavsar, an assistant professor in the Department of Medical Microbiology & Immunology. The problem has always been with the side-effects. Nearly 100 per cent of patients who receive higher doses of cisplatin show some degree of permanent hearing loss. The ability to prevent this side-effect would dramatically improve the quality of life of childhood cancer survivors after they recover from the disease.

As Bhavsar explains, many researchers look at cisplatin’s damaging side-effects from the angle of genetics, trying to determine underlying risk factors for hearing loss or examine how it works as a chemotherapeutic. A fair amount was known about the progression of hearing loss as a side-effect, but it was the initial spark—the instigating factor kicking everything off—that remained a mystery.

Bhavsar and his team thought outside the box and took things all the way back to the periodic table with their approach, getting some clues from the chemical composition of cisplatin itself and eventually identifying a particular receptor that was getting turned on.

The receptor in question is Toll-like receptor 4 (TLR4), which is involved in the body’s immune response. TLR4 works by crossing the cell membrane, sticking a portion of itself outside the cell to sample the environment and to look for different signals that indicate damage or danger of some sort.

“It’s a receptor that your body normally uses to detect when there’s some sort of issue, like an infection. This receptor will turn on, and it’ll start producing these signals that tell the cell it’s under stress. Unfortunately in the case of cisplatin, those signals ultimately lead to the death of the cells responsible for hearing.”

The cells affected by TLR4’s signals are located within the cochlea of the ear, where they play a crucial role in hearing, translating vibrations in the ear into electrical impulses. Cisplatin also accumulates in the kidneys, but the difference is that it can be flushed out and diluted in that area of the body; in a closed system such as the ear, it accumulates and damages the cells.

“These cells don’t renew. You really only get one shot and if they’re gone, you’re in trouble. The hearing loss is permanent,” said Bhavsar.

The only way to prevent the damage is to stop the signals TLR4 produces that lead to the accumulation of cisplatin. To confirm the efficacy of inhibiting the TLR4 receptor, Bhavsar and his team looked at zebrafish models, with the help of Ted Allison, an associate professor in the Department of Biological Sciences and member of the U of A’s Neuroscience and Mental Health Institute. They examined neuromasts, which are sensory cells within zebrafish that behave similarly to the human hair cells typically damaged by cisplatin. Bhavsar was able to prove that inhibiting TLR4 led to an inhibition of the damage on the sensory cells.

“These cells don’t renew. You really only get one shot and if they’re gone, you’re in trouble. The hearing loss is permanent…. (This research) really does open the door for potential therapeutics.”

Amit Bhavsar

Bhavsar, a member of the Cancer Research Institute of Northern Alberta (CRINA), the Li Ka Shing Institute of Virology and the Women and Children’s Health Research Institute (WCHRI), is collaborating with CRINA member Frederick West and Allison to refine an inhibitor that can disrupt this sampling process, removing the function that causes the toxic side-effect while still keeping the immune sensor function intact so patients don’t become immunocompromised. 

“It really does open the door for potential therapeutics,” said Bhavsar.

The study, “Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity,” was published in EMBO Reports. The work received support through operating grants from the Canadian Institutes of Health Research and the Stollery Children’s Hospital Foundation through WCHRI, as well as funding from the Li Ka Shing Institute of Virology.

Featured image: Amit Bhavsar © Photo: William Au

Provided by University of Alberta

Scientists At Tel Aviv University Develop New Gene Therapy for Deafness (Medicine)

Breakthrough may help in the treatment of children with hearing loss.

A new study from Tel Aviv University (TAU) presents an innovative treatment for deafness, based on the delivery of genetic material into the cells of the inner ear. The genetic material “replaces” the genetic defect and enables the cells to continue functioning normally.

Professor Karen Avraham and Shahar Taiber of Tel Aviv University © Tel Aviv University

The scientists were able to prevent the gradual deterioration of hearing in mice that had a genetic mutation for deafness. They maintain that this novel therapy could lead to a breakthrough in treating children born with various mutations that eventually cause deafness.

The study was led by Professor Karen Avraham of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. The paper was published in EMBO Molecular Medicine on December 22, 2020.

Deafness is the most common sensory disability worldwide. According to the World Health Organization, there are about half a billion people with hearing loss around the world today, and this figure is expected to double in the coming decades. One in every 200 children is born with a hearing impairment, and one in every 1,000 is born deaf. In about half of these cases, deafness is caused by a genetic mutation. There are currently about 100 different genes associated with hereditary deafness.

“In this study we focused on genetic deafness caused by a mutation in the gene SYNE4 – a rare deafness discovered by our lab several years ago in two Israeli families, and since then identified in Turkey and the UK as well,” Professor Avraham reports. “Children inheriting the defective gene from both parents are born with normal hearing, but they gradually lose their hearing during childhood. The mutation causes mislocalization of cell nuclei in the hair cells inside the cochlea of the inner ear, which serve as soundwave receptors and are essential for hearing. This defect leads to the degeneration and eventual death of hair cells.”

A 3D rendering of a hair cell of a treated mouse. The nucleus is stained in blue, the cytoskeleton is stained in green, and Nesprin 4 is stained in red. © Shahar Taiber, Tel Aviv University

“We implemented an innovative gene therapy technology: we created a harmless synthetic virus and used it to deliver genetic material – a normal version of the gene that is defective in both the mouse model and the affected human families,” says Shahar Taiber, one of Professor Avraham’s students on the combined MD-PhD track. “We injected the virus into the inner ear of the mice, so that it entered the hair cells and released its genetic payload. By so doing, we repaired the defect in the hair cells and enabled them to mature and function normally.”

The treatment was administered soon after birth and the mice’s hearing was then monitored using both physiological and behavioral tests. “The findings are most promising,” says Professor Jeffrey Holt from Boston Children’s Hospital and Harvard Medical School, a collaborator on the study. “Treated mice developed normal hearing, with sensitivity almost identical to that of healthy mice who do not have the mutation.”

The scientists are now developing similar therapies for other mutations that cause deafness.

Microscopy image of the mouse cochlea: Hair cells are stained in red and cells transduced by the virus are stained in green. © Shahar Taiber, Tel Aviv University

 “This is an important study that shows that inner ear gene therapy can be effectively applied to a mouse model of SYNE4 deafness to rescue hearing,” says Professor Wade Chien, MD, from the NIDCD/NIH Inner Ear Gene Therapy Program and Johns Hopkins School of Medicine, who was not involved in the study. “The magnitude of hearing recovery is impressive. This study is a part of a growing body of literature showing that gene therapy can be successfully applied to mouse models of hereditary hearing loss, and it illustrates the enormous potential of gene therapy as a treatment for deafness.”

Additional contributors included Professor David Sprinzak from the School of Neurobiology, Biochemistry and Biophysics at TAU’s George S. Wise Faculty of Life Sciences. The study was supported by the US-Israel Binational Science Foundation, the National Institutes of Health, the European Research Council, and the Israel Precision Medicine Partnership Program of the Israel Science Foundation.

The research paper is available at the journal’s web site here.

Reference: Shahar Taiber, […], Karen B Avraham et al., “Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness”, EMBO Mol Med (2020)e13259 https://doi.org/10.15252/emmm.202013259

Provided by Tel Aviv University


Tel Aviv University (TAU) is a globally top-ranked university, a leading research institution, and a center of discovery. As Israel’s largest public institution of higher learning, TAU is home to 30,000 students, including 2,100 international students from over 100 countries. The University encompasses nine faculties, 35 schools, 400 labs, and has 17 affiliated hospitals in its network.

Molecular Switch Controls Ability to Repair Hearing Loss in Mice (Neuroscience)

In a study in mice, Johns Hopkins Medicine researchers have found a molecular switch that turns off the animal’s ability to repair damaged cells in the inner ear. The findings shed light on regenerative abilities that are present in many species of birds and fish, but get turned off in mammals, including humans.

Photomicrograph showing a cross section of the wall of a mouse cochlea, a bony structure within the inner ear. The hair cells on top capture sound waves. In a new study, Johns Hopkins Medicine researchers found that a molecular “switch” within the supporting cells seen at the bottom of the photo may be able to turn on and off the ability to repair damaged hair cells. Credit: Division of Neurology, Johns Hopkins Medicine

The study was published Sept. 8, 2020, in The Proceedings of the National Academy of Sciences.

“We might have for the first time identified something that explains why humans lost the ability to repair cells related to hearing loss,” says Angelika Doetzlhofer, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine, and co-author of the study.

More than 37 million adults in the United States report hearing loss. In the majority of cases, it results from damage to sound receptor cells deep within the human ear known as hair cells. These cells line the spiral-shaped walls of the cochlea, a bony structure in the inner ear, and capture sound waves reverberating in the area. Then, they convert the vibrations into electrical impulses that are carried to the brain by nerves.

Hair cells are kept healthy by a layer of cells called supporting cells. In birds and fish, supporting cells can function as progenitors to replace lost hair cells. Recent studies of mammals have shown that supporting cells have some regenerative potential early in life, before the animals start hearing. For example, supporting cells in mouse pups are able to create new hair cells at birth. However, the ability to repair or replace them stops within a week. At that point, any damage done to the hair cells is irreversible.

Based on these data from previous mouse studies, Doetzlhofer and study co-author Xiaojun Li, Ph.D., a postdoctoral fellow in her laboratory, looked to the rodents as a way to better understand what controls the decline in regenerative ability in mammals.

The researchers achieved this by following the levels of a protein and micro RNA in mice, called LIN28B and let-7, respectively. LIN28B and let-7 are what scientists call “mutual agonists,”‘ meaning they control each other’s function within the cell.

They found that when let-7 levels ramp up, LIN28B levels drop at the same time, turning off the mouse’s regenerative ability.

The two researchers found that without LIN28B, hair cell regeneration does not occur. They tested this by using cochlear tissue and cells from genetically engineered mice that enabled the protein and its agonistic RNA to be turned on and off as needed.

The researchers say that their findings suggest LIN28B is the deciding factor as to whether or not the hair cells retain their regenerative abilities. LIN28B, they believe, promotes the regenerative process by turning on progenitor-specific genes in supporting cells, which then reprograms supporting cells into hair cell progenitor-like bodies.

“The most exciting part was seeing the dramatic effects of manipulating these factors. We began the experiment hoping to get any type of response, and to see a restoration regeneration capability was really thrilling,” says Doetzlhofer.

The researchers say that a better understanding of the biology behind hair cell regeneration may lead to the development of future treatments for hearing loss.

References: Xiao-Jun Li, Angelika Doetzlhofer, “LIN28B/let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling”, Proceedings of the National Academy of Sciences Sep 2020, 117 (36) 22225-22236; DOI: 10.1073/pnas.2000417117 https://www.pnas.org/content/117/36/22225

Provided by Johns Hopkins University

Non-hereditary Mutation Acts as Natural Gene Therapy in Patient with Rare Disease (Biology)

Scientists at a research center supported by FAPESP identified a non-inherited mutation in blood cells from a patient with GATA2 deficiency that may have prevented bone marrow failure and other clinical manifestations.

Researchers affiliated with the Center for Cell-Based Therapy (CTC (http://ctcusp.org/rationale-2/presentation)) in Ribeirão Preto, Brazil, have identified for the first time a non-hereditary mutation in blood cells from a patient with GATA2 deficiency, a rare autosomal disease caused by inherited mutations in the gene that encodes GATA-binding protein 2 (GATA2). GATA2 regulates the expression of many genes that play a key role in developmental processes and cell renewal.

Lung tissue from patient with GATA2 deficiency, displaying pulmonary alveolar proteinosis and inflammatory lymphoplasmacytic infiltrate. ©CTC

The researchers believe the non-hereditary (somatic) mutation may have acted as a kind of natural gene therapy, preventing the disease from damaging the process of blood cell renewal (hematopoiesis), so that the patient did not develop such typical clinical manifestations as bone marrow failure, hearing loss and lymphedema (blockage of the lymphatic system).

An article on the study is published (https://ashpublications.org/blood/article-abstract/136/8/1002/461035/Somatic-genetic-rescue-in-hematopoietic-cells-in?redirectedFrom=fulltext) in the journal Blood, featuring on the cover and with an editorial commentary (https://ashpublications.org/blood/article/136/8/923/463248/Natural-gene-therapy-in-hematopoietic-disorders).

The findings pave the way for the use of gene therapy and changes in genetic counseling for families with the hereditary disorder. “When a germline [inherited] mutation in GATA2 is detected, the patient’s family has to be investigated because there may be silent cases,” Luiz Fernando Bazzo Catto, first author of the article, told.

CTC is a Research, Innovation and Dissemination Center (RIDC (https://cepid.fapesp.br/en/home)) funded by São Paulo Research Foundation – FAPESP and hosted by the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP), where Catto is a PhD candidate. His thesis advisor is Professor Rodrigo Calado (https://bv.fapesp.br/en/pesquisador/43043/rodrigo-do-tocantins-calado-de-saloma-rodrigues), corresponding author of the article and a member of CTC.

The patient was identified when his two sons were undergoing medical treatment at the blood center of the hospital run by FMRP-USP. One of the siblings was diagnosed with moderate aplastic anemia (a bone marrow disorder in which the body stops producing enough new blood cells) and psoriatic arthritis. His low red blood cell count and immune cell deficiency worsened over the following five years and he died aged 27 from a lung infection. Post-mortem DNA sequencing confirmed his germline mutation and GATA2 deficiency diagnosis.

His brother began treatment at the hospital aged 25, with a history of recurrent lung infections, hypothyroidism, deep-vein thrombosis and deafness. Sequencing of his leukocytes and skin fibroblasts also confirmed an identical germline mutation.

To find out from which parent the brothers inherited the mutation, the researchers sequenced the mother’s and father’s DNA. The mother did not have the mutation. The 61-year-old father had exactly the same mutation as his sons in sperm and skin fibroblasts. He was asymptomatic, and his blood count and lymphocytes were within the normal range.

“This discovery raised the question whether the father transmitted the mutation or acquired it but didn’t pass it on to his sons,” Catto said.

In search of an answer, the researchers used next-generation sequencing to estimate the proportion of normal blood cells in the father’s bone marrow, preventing clinical manifestations of GATA2 deficiency, and of cells similar to his children’s.

The results showed that 93% of his leukocytes had the somatic mutation that confers protection from the clinical manifestations of GATA2 deficiency. The remaining 7% carried the mutation associated with the disorder. “This 7% were a remnant of the original clone,” Catto said.

Treatment prospect

The researchers also sequenced the father’s T-lymphocytes, which are long-lived, to find out whether his somatic mutation could induce normal cell production for a long time. The analysis showed that the somatic mutation occurred early in their lives and in the development of hematopoietic stem cells, which have the potential to form blood. “It’s very likely that the father had acquired the somatic mutation in his blood a long time ago,” Catto said.

To see if the father’s blood cells could maintain the activity for a long time, they measured the telomeres of his peripheral blood leukocytes. Telomeres are repetitive sequences of non-coding DNA at the tip of chromosomes that protect them from damage. Each time cells divide, their telomeres become shorter. They eventually become so short that division is no longer possible, and the cells die or become senescent.

The telomeres analyzed by the researchers were long. “This indicates that these blood cells can remain active for a long time,” Catto said.

A hypothesis formulated in the article is that the existence of the somatic mutation in the father’s blood cells, and its restoration of the blood cell renewal process, may have contributed to the non-manifestation of extra-hematological symptoms of GATA2 deficiency such as deafness, lymphedema, and thrombosis. Early hematopoietic recovery in patients with the disease, via a bone marrow transplant or in future via gene therapy, could be beneficial and avoid other clinical complications, the authors suggest in the article on the study.

“A sort of natural gene therapy occurred in this patient,” Calado said. “It’s as if he embodied an experiment and a medium-term prospect of analogous gene therapy treatment in patients with GATA2 deficiency.”

Besides contributing to an advance in treatment of the disease and genetic counseling, the study also provides new knowledge about the biology of hematopoietic stem cells. “The findings help us understand better how stem cells can recover by repairing an initial genetic defect,” Calado said.

References: Luiz Fernando B. Catto, Gustavo Borges, André L. Pinto, Diego V. Clé, Fernando Chahud, Barbara A. Santana, Flavia S. Donaires, Rodrigo T. Calado; Somatic genetic rescue in hematopoietic cells in GATA2 deficiency. Blood 2020; 136 (8): 1002–1005. doi: https://doi.org/10.1182/blood.2020005538

Provided by FAPESP

Opioid Use Can Cause Partial or Full Deafness (Medicine)

According to new research done by Mozeika and colleagues, opioid receptors in the inner ear can cause partial or full hearing loss.

Fig: Inner ear anatomy. Image credit: Medical Gallery of Blausen Medical 2014, doi: 10.15347/wjm/2014.010.

For the new study, the researchers reviewed records from the New Jersey Poison Control Center from 1999 to 2018 to determine the association between opioid use and degrees of hearing loss.

They identified 41 people with opioid exposure who experienced full or partial hearing loss or tinnitus, likely caused by toxicity to the ear.

More than half had used heroin, followed by oxycodone, methadone and tramadol; 88% had only one known exposure.

Most people reported the condition affecting both ears, with 12 people experiencing deafness, 15 partial or total loss of hearing acuity, 10 tinnitus and four a mix of symptoms.

While some people may regain their hearing, the loss could be permanent with others — 21% of those reporting the condition had no improvement in hearing when they were discharged from the hospital.

The delicate structures of the inner ear are very susceptible to injury if oxygen supply is insufficient, as well as to the direct effect of toxins like opioids.

Although the study found a link with heroin, toxicity to the ear can occur with every opioid. This study supports what has been found in animal studies, which is that any opioid can cause hearing loss.

This might be because we already have built-in opioid receptors, or binding sites, in the inner ear. Activating them may trigger this injury in some patients.

References: Mozeika, A.M., Ruck, B.E., Nelson, L.S. et al. Opioid-Associated Hearing Loss: A 20-Year Review from the New Jersey Poison Center. J. Med. Toxicol. (2020). https://doi.org/10.1007/s13181-020-00785-5 link: https://link.springer.com/article/10.1007%2Fs13181-020-00785-5