TMPRSS3

Advances in understanding the many different genetic causes of childhood-onset hearing loss indicate that genomic testing could assist in individualizing treatment planning, including the optimal timing of treatment. New findings show that genetic testing is a valuable tool in determining prognosis for a child's hearing loss and in predicting how useful a cochlear implant could be for that child's understanding of speech. With genetic diagnosis, it is possible to anticipate future hearing loss across sound frequencies, progression with age, and severity. Advances in understanding the many different genetic causes of childhood-onset hearing loss indicate that genomic testing could assist in treatment planning, including optimal timing of treatment. Even if a child with hearing loss did not receive a diagnosis from genetic testing a few years ago, very rapid recent progress in genomics makes re-testing worthwhile, according to scientists in this field. Hearing loss, usually stemming from sensory problems in the inner ear, affects about 1 in 400 newborns in the United States. About half of these children have a genetic cause for their hearing loss. More than 120 genes and thousands of different genetic variants can lead to childhood hearing loss. Virtually all children with genetic hearing loss have a mutation or mutations in only one gene. A recent study, reported Jan. 12 in JAMA Otolaryngology-Head & Neck Surgery, examined a group of more than 400 youngsters with bilateral sensorineural hearing loss affecting both ears. The researchers from UW Medicine and Seattle Children's Hospital sought to identify the genetic causes of hearing loss in this group and how each genetic cause relates to a specific type of hearing loss. They also evaluated whether the genetic cause of hearing loss was related to the success of treatment with a cochlear implant, a surgically placed electronic device that enables a person to sense sound through impulses transmitted to the brain. The findings show that genetic testing is a valuable tool in determining prognosis for a child's hearing loss and in predicting how useful a cochlear implant could be for that child's understanding of speech. "With genetic diagnosis, it is possible to anticipate future hearing loss across sound frequencies and progression with age," the researchers noted in their paper. "This information can be integrated with current severity of hearing loss to decide on treatment." The study was led by Ryan J. Carlson, an M.D./Ph.D. student in the Medical Scientist Training Program at the University of Washington School of Medicine in Seattle. It was conducted during his training with Mary-Claire King, the senior author and professor of medicine and genome sciences at the UW School of Medicine and with Jay Rubinstein, professor of otolaryngology and head and neck surgery at the UW School of Medicine. "For more than half of pediatric patients, genomic testing can now identify a genetic cause for their hearing loss and often provide critical information on its clinical characteristics," explained Carlson. The study participants included 449 children from 406 families. Genomic analysis resulted in genetic diagnoses for 210 of the 406 families, including 55 of the 82 families with more than one child with hearing loss and 155 of the 324 families with a single child with hearing loss. Rates of genetic diagnosis were similar for all ancestries in the study group. In this study population, the researchers detected variants responsible for hearing loss in 43 different genes. With one exception, each child's genetic diagnosis involved only one gene. The severity of hearing loss, the sound frequencies most affected, and changes in hearing loss over time varied by gene, and, in some cases, by the type of variant within the gene. Children with causative mutations in the genes MYO6, OTOA, SLC2644, TMPRSS3, or the most severe mutations in the GJB2 gene had progressive hearing loss. All of the children who had cochlear implants had better speech perception than before they received their implants. The degree of success of the cochlear implant varied somewhat based on the participant's genetic diagnosis. Taking into account the age of the child at implant and the length of time the implant was in place, speech perception was highest for children whose hearing loss was due to mutations in the MITF or TMPRSS3 genes. However, the researchers concluded that differences in success of cochlear implants related to the genetic diagnosis was not substantial enough to preclude a cochlear implant for any patient who otherwise met the implant criteria. Ancestries of the study participants were 17 (4%) African/African American, 32 (8%) East Asian, 219 (54%) European, 53 (13%) Latinx, 16 (4%) South Asian, and 61 (15%) who reported more than one ancestry. Slightly more than half (51%) of the children in the study were female The study was conducted from 2019 to 2022 at the otolaryngology and audiology clinics at Seattle Children's Hospital and the University of Washington, including the Center for Human Development and Disability. DNA from the participants was analyzed by genomic sequencing and structural variant analysis in Mary-Claire King's genome sciences laboratory at the UW School of Medicine. Severity and progression of their hearing loss was measured through audiological testing, and success of their cochlear implant was evaluated by pediatric or adult speech perception testing. The research team outlined several key conclusions from their findings: First, genetic testing for hearing loss can identify a genetic cause in most pediatric patients. Newborn hearing screening misses hearing loss in about one-third of affected children, because the hearing loss is not yet detectable at birth. Genetic testing could resolve that gap. Second, technologies for genomic analysis are improving rapidly. If a child has already had genetic testing, with negative results, re-testing may find a genetic cause that was previously missed. Third, genetic testing can identify syndromic forms of hearing loss and lead to necessary referrals of children to key specialists. Finally, genetic diagnoses can be more effectively used to inform precision treatment for childhood hearing loss. Once the expected clinical characteristics of a certain genetic cause is known, that information can be used to evaluate prognosis and guide treatment. Overall, the researchers emphasized, "Detection of hearing loss at the earliest possible age is important for cognition and social development, regardless of management approach." Carlson noted that the study had a direct positive impact for its participants. "We were able to provide genetic testing for over 400 families with hearing loss in this one study. Many participants received new genetic diagnoses that were important to their care," he explained. "I am proud to have directed a project that provided both direct benefits for those involved and indirect benefits for all patients with hearing loss." The study was funded by National Institute of Health grants 2R01DC011835, 30DC018702, T32DC005361, T32DC000018, and T32GM007266 as well as grants from the ARCS Foundation, Ben B. Cheney Foundation, and Virginia Merrill Bloedel Hearing Research Center.

A growing gene therapy company is teaming up with one of the largest gene therapy manufacturers to get its drug into patients in clinical trials. Myrtelle announced on Monday that it inked a deal with Forge Biologics to make Myr-201, a gene therapy indicated for monogenic hearing loss. The target patient population, Myrtelle said, is people with a type of hearing loss called DFNB8, or autosomal recessive deafness 8. Forge will provide plasmid manufacturing, plus cGMP AAV process development and scaling manufacturing services at its manufacturing site in Columbus, OH, Myrtelle said in a press release. As that gets underway, Myrtelle said it plans on moving development efforts forward into Phase I/II clinical trials. The neurological disease-focused biotech recently in-licensed the candidate in May from Rescure Hearing, a preclinical gene therapy outfit. The therapy is designed to work by delivering a copy of the TMPRSS3 gene straight into the inner ear. Myrtelle is not the only company focused on gene therapies for hearing loss. Decibel Therapeutics has been in preclinical studies for its hearing loss gene therapies while recently touting early clinical stage data for a candidate to protect against chemotherapy-induced hearing loss. The new deal with Myrtelle comes on the heels of Forge securing a $90 million Series C round last month, bringing the total amount it’s raised so far to $330 million. Forge CEO Tim Miller told Endpoints News in September that the round only took a few months to put together as firms had already approached the gene therapy manufacturer. Forge Biologics continues its hot streak with $90M round to boost gene therapy manufacturing services

Plasmid and AAV Manufacturing Partnership to Advance Myrtelle’s Novel Gene Therapy for Monogenic Hearing Loss for Phase 1/2 Clinical Trials WAKEFIELD, Mass. & COLUMBUS, Ohio--(BUSINESS WIRE)-- Myrtelle Inc., (Myrtelle), a clinical stage gene therapy company focused on developing transformative treatments for neurodegenerative diseases, and Forge Biologics, a gene therapy-focused contract development and manufacturing organization, today announced a manufacturing partnership that will advance Myrtelle’s novel gene therapy for monogenic hearing loss, Myr-201, into clinical trials for patients with autosomal recessive deafness 8 (DFNB8). This press release features multimedia. View the full release here: Forge will provide research-grade and GMP-Pathway plasmid manufacturing services as well as cGMP adeno-associated viral (AAV) process development and scale-up manufacturing services for Myrtelle’s program, Myr-201. The program will utilize Forge’s platform process including its proprietary HEK 293 suspension Ignition Cells™ and pEMBR™ adenovirus helper plasmid. All development and cGMP manufacturing activities will occur at the Hearth, Forge’s 200,000 square foot gene therapy cGMP facility in Columbus, Ohio. “We are thrilled to be collaborating with Myrtelle to help them accelerate this novel gene therapy for monogenic hearing loss to patients,” said Timothy J. Miller, Ph.D., CEO, President, and Co-Founder of Forge Biologics. “This collaboration showcases the full end-to-end capabilities Forge is providing to gene therapy clients. We believe that employing our plasmid manufacturing, coupled with our suite of cGMP AAV manufacturing capabilities and expertise, will help support Myrtelle’s gene therapy technology and skills, enabling this novel therapy to reach those who need it the most.” Myrtelle entered into a worldwide exclusive licensing agreement with Rescure Hearing Inc. (RHI), a private, preclinical stage gene therapy company focusing on diseases affecting human hearing to develop a novel gene therapy for DFNB8 genetic hearing loss that includes low-dose recombinant adeno-associated virus (rAAV) gene therapy delivery of a therapeutic TMPRSS3 (transmembrane protease, serine 3) gene by local administration directly to the inner ear. Across its gene therapy programs, Myrtelle utilizes direct administration of low-dose gene therapy to target key cell types involved in the disorder, thereby avoiding immune-related and off-target effects that can arise with high-dose gene therapy administration delivered systemically. This strategy, currently being developed for Myrtelle’s central nervous system (CNS) programs, can be leveraged to other therapeutic areas outside the CNS, including adjacent and related areas such as the ear where local gene therapy delivery is potentially advantageous for hearing loss disorders such as DFNB8. Preclinical studies in the mouse model of DFNB8-mediated deafness have demonstrated that delivery of a wild type TMPRSS3 gene was able to promote hair cell and neuron survival and improve hearing function. "This collaboration is an important milestone in Myrtelle’s evolution as we seek to advance our novel gene therapy for monogenic hearing loss which has the potential to become a life-changing genetic medicine,” said Mark Pykett, Chief Executive Officer of Myrtelle. “Partnering with Forge Biologics, a leader in gene therapy manufacturing, and leveraging their AAV expertise, technology, and exceptional facility will support Myrtelle’s development efforts as we move into Phase 1/2 clinical trials with the goal of bringing this transformational therapy to patients in need.” About DFNB8 Individuals with mutations in TMPRSS3 present with two phenotypes: DFNB10-associated hearing impairment that is pre-lingual and DFNB8-associated hearing impairment that is typically late-onset and post-lingual. TMPRSS3 mutations can be divided into mild or severe; the combination of two severe mutations causes profound pre-lingual hearing loss, whereas milder mutations lead to less severe post-lingual hearing loss. About Myrtelle Myrtelle Inc. is a gene therapy company focused on developing transformative treatments for neurodegenerative diseases. The company has a proprietary platform, intellectual property, and portfolio of programs and technologies supporting innovative gene therapy approaches for neurodegenerative diseases. Myrtelle has an exclusive worldwide licensing agreement with Pfizer Inc. for its Canavan disease program. For more information, please visit the Company’s website at: . About Forge Biologics Forge Biologics is a hybrid gene therapy contract manufacturing and clinical-stage therapeutics development company. Forge’s mission is to enable access to life changing gene therapies and help bring them from idea to reality. Forge’s 200,000 square foot facility utilizes 20 cGMP suites in Columbus, Ohio, the Hearth, to serve as its headquarters. The Hearth is a custom-designed cGMP facility focused on AAV manufacturing and can host end-to-end manufacturing services to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing. By taking a patients-first approach, Forge aims to accelerate the timelines of these transformative medicines for those who need them the most. To learn more, visit .