Application of insulin-like growth factor-1 in the treatment of inner ear disorders

Abstract

Sensorineural hearing loss (SNHL) is considered an intractable disease, given that hair and supporting cells (HCs and SCs) of the postnatal mammalian cochlea are unable to regenerate. However, with progress in regenerative medicine in the 21st century, several innovative approaches for achieving regeneration of inner ear HCs and SCs have become available. These methods include stem cell transplantation, overexpression of specific genes, and treatment with growth factors. Insulin-like growth factor-1 (IGF-1) is one of the growth factors that are involved in the development of the inner ear. Treatment with IGF-1 maintains HC numbers in the postnatal mammalian cochlea after various types of HC injuries, with activation of two major pathways downstream of IGF-1 signaling. In the aminoglycoside-treated neonatal mouse cochlear explant culture, promotion of the cell-cycle in SCs as well as inhibition of HC apoptosis was observed in the IGF-1-treated group. Activation of downstream molecules was observed in SCs and, in turn, SCs contribute to the maintenance of HC numbers. Using comprehensive analysis of the gene expression, the candidate effector molecules of the IGF-1 signaling pathway in the protection of HCs were identified as Netrin1 and Gap43. Based on these studies, a clinical trial has sought to investigate the effects of IGF-1 on SNHL. Sudden SNHL (SSHL) that was refractory to systemic steroids was treated with IGF-1 in a gelatin hydrogel and the outcome was compared with a historical control of hyperbaric oxygen therapy. The proportion of patients showing hearing improvement was significantly higher in the IGF-1-treatment group at 24 weeks after treatment than in the control group. A randomized clinical trial is ongoing to compare the effect of IGF-1 treatment with that of intra-tympanic steroids for SSHL that is refractory to systemic steroids.

Growth factor and receptor malfunctions associated with human genetic deafness

“…Genetic studies of hundreds of genes necessary for audition have uncovered several pathways important for normal hearing. Based initially upon studies of animal model, growth factors are now being explored for treatment of noise and ototoxic induced deafness and age-related hearing loss, [100][101][102][103][104][105][106][107][108][109] and some of these are currently in clinical trials. 110,111 For example, topical application of IGF1 to the middle ear was used to treat sudden sensorineural hearing loss in humans, and some treated individuals showed improvements of 10 to 30 dB for tested frequencies as compared to controls.…”

“…110,111 For example, topical application of IGF1 to the middle ear was used to treat sudden sensorineural hearing loss in humans, and some treated individuals showed improvements of 10 to 30 dB for tested frequencies as compared to controls. 103,112 Hair cell regeneration in response to application of growth factors and by inhibition of specific signaling pathways is also being explored. 113 For example, an inhibitor of NOTCH signaling is in phase II clinical trial for treatment of sensorineural moderate to severe hearing loss.…”

GRHL2 genetic polymorphisms may confer a protective effect against sudden sensorineural hearing loss

“…Vascular occlusion is a potential cause of impaired cochlear perfusion, and risk factors, including factor V Leiden and prothrombin G20210A that lead to vascular perfusion defects, are also suspected to be important in SSHL (22)(23)(24). By contrast, inner ear damage was also associated with SSHL and Yamamoto et al reported that insulin-like growth factor-1, a growth factor involved in the development of the human inner ear, enhanced the regeneration of hair cells damaged in SSHL (25). Genetic factors associated with SSHL have generated significant interest.…”

A Comparative Study of Metabolic Disorders in Vertigo

“…This is further supported by clinical trial of IGF-1 treatment on human SSHL as well as in vivo animal experiments, which has confirmed its efficacy in hair cell injuries. 15 In a recent study, fractionated diet with glucose restriction was effective for the treatment of vestibular dysfunction associated with glucose metabolism disorders. 16 Disorders of glucose metabolism are considered the most common aetiology of metabolic labyrinthine disorders as per previous studies.…”