Critical Review Sensorineural Hearing Loss: Potential Therapies and Gene Targets for Drug Development Louisa S. Tang, Celina Montemayor and Fred A. Pereira Huffington Center on Aging, Bobby R. Alford Department of Otolaryngology – Head and Neck Surgery, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA Summary Recent advances in the developmental biology, genetics and cell biology of the inner ear are guiding research to novel therapeutic modalities – a market currently estimated to be at least US$10 billion. This article highlights prospects to manipulate the mam- malian hearing organ with gene and stem cell delivery to the inner ear to protect, repair or regenerate the hair cells, supporting cells and associated nerves. IUBMB Life, 58: 525–530, 2006 Keywords Age-related hearing loss, cochlea, hair cells, regenera- tion, cell cycle, gene therapy, stem cells. INTRODUCTION According to the World Health Organization (WHO), in 2002 hearing loss and deafness affected at least 250 million people worldwide and is becoming an increasing challenge to public health as lifespan increases and the general population ages (1, 2). Moreover, increased exposure to noise at the workplace and increased use of portable electronic devices is contributing to higher incidence of hearing impairment (3). The WHO has estimated that by 2050, hearing loss will rise to 900 million worldwide (2). Those affected with sensory impairments suffer a lower quality of life. Management of communication disorders (hearing and voice/resonatory dis- orders) can involve multiple medical specialties (4). These include otolaryngology, speech-language pathology and audiology, neurology, neurosurgery, psychiatry, physical medicine and rehabilitation, and other medical-surgical dis- ciplines. Loss in productivity and management of these disorders bears a great economic cost, estimated to equal 3% ($186 billion) of the US gross national product in 2000 (4). The mammalian ear contains special sense organs that govern hearing and balance; their roles are dependent on a few thousand specialized mechanosensory hair cells and their innervation. These hair cells are sensitive to a multitude of genetic and environmental factors. Many hearing disorders involve irreversible damage to hair cells and their associated nerves and result in permanent hearing impairment. This condition is known as sensorineural hearing loss. Although prosthetic devices such as hearing aids and cochlear implants are available, there are currently no drugs or other biological interventions to treat deafness due to hair cell loss. RISK FACTORS FOR HEARING LOSS Deafness is a relatively common disorder, with approxi- mately 1 in 1000 children born with a serious permanent hear- ing impairment (5) and single-gene defects account for over half of the cases of childhood deafness (6). In the US, about 33 births a day or 12,045 children are born annually with hearing loss and about 10% of the adult population is affected by some degree of hearing loss (7). Hearing loss is caused by genetic and non-genetic factors. Inherited forms may be associated with a syndromic or non-syndromic disease (8). The major non-genetic causes of sensorineural hearing loss include exposure to noise, ototoxic drugs and viral or bacterial infections. Exposure to continuous occupational and environ- mental noise levels in excess of 75 – 80 dB is sufficient to pose a risk of hearing loss. The risk increases as noise level, duration and number of exposures increase (9, 10). Noise can also interact synergistically with some ototoxic agents (each of which can cause hearing loss) including aminoglycoside anti- biotics (e.g., streptomycin), loop diuretics (e.g., ethacrynic acid), antithyroid and antitumor drugs (e.g., cisplatin), excita- tory amino acids (e.g., glutamate), or common antibiotics such as erythromycin and polymyxin B (9 – 12). Bacterial and viral Received 12 June 2006; accepted 17 July 2006 Address correspondence to: Fred A. Pereira, PhD, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel: þ1 713 798 6933. Fax: þ1 713 798 1610. E-mail: fpereira@bcm.edu IUBMB Life, 58(9): 525 – 530, September 2006 ISSN 1521-6543 print/ISSN 1521-6551 online Ó 2006 IUBMB DOI: 10.1080/15216540600913258