Disease Burden
Background and significance of the research nationally and internationally
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. Moreover, increased exposure to noise at the workplace and increased use of portable electronic devices is contributing to higher incidence of hearing impairment. The WHO has estimated that by 2050, hearing loss will rise to 900 million worldwide. In EU, there were over 44 million citizens suffer hearing loss and 40 000 profoundly hearing loss. Those affected with sensory impairments suffer a lower quality of life.
Inner ear is a clinically vital target, well representing the central nervous system and other difficult-to-access body sites; it is isolated, multicompartmental with neural, supporting and vascular targets, and relatively immunoprivileged. Measures of function and structural integrity are quantitative, precise, and objective, permitting detection of loss of a single sensory cell. Cochlear and vestibular hair cell regeneration has been proved even in mammalian. The vectors applied in the literature are virus, which is high risk for the human body. The goal of our project is to develop nanoparticle therapeutics, which are targetable to selected cell populations, biodegradable, and high efficacy of transfection by biological surface modification.
How is the inner to be damaged?
The auditory system seems better equipped to deal with injuries in lower species than in mammals. In fish and amphibians, the inner ear will produce new sensory cells (hair cells) throughout their life and, consequently, injured cells can be replaced continuously. Birds lose this ability during embryonic development, but instead possess the capacity to replace the injured sensory cells by regeneration and thus maintain hearing function. In contrast, mammalian hair cell loss has always been considered irreversible. The mechanism of cell death in the cochlea is produced in two ways; through necrotic cell death mediated by very loud noise, or apoptosis, mediated by the activation of cysteine protease family within the cells, the caspases (very loud noise can also induce immediate apoptosis). Originally these mechanisms, necrosis vs apoptosis, were thought to operate with different initiators (as extrinsic cellular pathway and intrinsic cellular pathway, respectively), but assumingly these mechanisms are more or less under statistical control in that dependent on stimulus the wealth of cell death and damages are operated with one of these two major mechanisms. Each of these mechanisms provides the possibility to reduce and, in some cases, to prevent cochlear cell death through active intervention with pharmacotherapy.
Can the inner ear be repaired?
Recently, many researchers have investigated the role of antioxidant agents in different models of peripheral hearing disorders. It has been found that antioxidants protect the cochlea from noise-induced trauma, as well as cisplatin and aminoglycoside exposure.Van De Water et al. recently suggested that protection of auditory sensory cells from cisplatin is carried out at the molecular level by three mechanisms: prevention of ROS formation; neutralisation of toxic products, and blockage of apoptotic pathways. Several genes regulate the differentiation of cochlear hair cells and supporting cells from their common precursor cells during mammalian embryogenesis. Recent experiments have provided new and exciting information about the processes related to inner ear damage. For example, in the mammalian vestibular system, hair cell regeneration has been shown to occur under certain circumstances . The situation in the auditory system is less clear. There is evidence of hair cell regeneration in newborn mice given explants of cochlear duct and in replacing the damaged hair cells by converting the supporting cells. A key gene is Atoh1 (also known as Math 1). This is the mouse homologue of the Drosophila gene atonal, that encodes a basic helix-loop-helix transcription factor. Overexpression of Atoh 1 in nonsensory cells of the normal cochlea generates new hair cells, both in vitro and in vivo. Atoh 1 has been shown to act as a "pro-hair cell gene" and is required for the differentiation of hair cells from multipotent progenitors. Recently Izumikawa et al (2005)demonstrated that in mammals by using gene therapy the lost hair cells will regenerate and that hearing may be returned to the profoundly deaf mammalian ear. This finding opens new perspectives for the treatment of hearing loss and justifies the efforts to encapsulate nucleotides encoding the Math 1 gene within the nanostructures for the treatment of deafness. In addition, a moderate degree of spontaneous recovery of hearing after noise trauma has been observed in humans, implying that humans may also have the capacity to regain hearing function. However, the mechanisms behind the recovery have not yet been fully delineated. There is, however, substantial evidence that cochlear damage induced by noise can be prevented by the application of different pharmacologically active substances. Thus, there are grounds to expect that hearing disorders in mammals may, under certain circumstances, be successfully treated. Drugs can reach the inner ear by systemic application (orally, intravenously or via the cerebrospinal fluid (CSF)) or locally (from the middle ear over the round window membrane (RWM) through permeation, direct injection through the RWM or the oval window and also with an osmotic pump by passing through the lateral wall of the cochlea). However, not all of these approaches are clinically possible.
Previous research pertaining to project topic
Round window characteristics
On of the key elements in the administration of the drugs to treat inner ear disorders is the permeation of the round window membrane. The ultra fine structure of the round window membrane is still poorly known. We have studied the ultrastructure of round window membrane in human, rat and guinea pig, and found that there plenty of vesicles in the round window membrane. This indicates that clathrin and caveolin pathways can be involved in the transportation of NPs through round window membrane.
Targeting
The specific cell targeting of NP represents another challenge. We will overcome this with targeting ligands, which will bind to specific receptors present on spiral ganglion cells ( the trk-B receptors) and on the vasculature (the matrix metalloproteins, MMP2). Peptide will be identified with a phage display technique. Such peptide screening is termed biopanning, and results in highly selective peptides binding to specified receptors, thus allowing accurate targeting.
Gene therapy
Several genes regulate the differentiation of cochlear hair cells and supporting cells, during mammalian embryogenesis, from their common precursor cells. A key gene is known to be Atoh 1 (also known as Math 1). This is the mouse homolog of the Drosophila gene atonal, that encodes a basic helix-loop-helix transcription factor. Over expression of Atoh 1 in non-sensory cells of the normal cochlea generates new hair cells, both in vitro and in vivo. Atoh 1 has been shown to act as a "pro-hair cell gene" and is required for the differentiation of hair cells from multi-potent progenitors. Recently our adjunct research institute demonstrated that in mammals, by using gene therapy, the lost hair cells will regenerate and also return hearing to the profoundly deaf mammalian ear. This finding opens new perspectives for treatment of hearing loss and justifies the efforts to encapsulate nucleotides encoding the Math 1 gene within the nanostructures. Math1 (Atoh1) is necessary in re-specifying supporting cells and in biasing post-mitotic cells toward the hair cell fate during hair cell regeneration.
