The blood-labyrinth barrier to treat sensorineural hearing loss

The blood-labyrinth barrier, a new therapeutic target for the treatment of rare sensorineural hearing losses

Researchers from the Hearing Neuropathology and Myelinopathies group and Pilar López-Larrubia of the Sols-Morreale Biomedical Research Institute (CSIC-UAM) have published novel data on the alteration of the permeability of the blood-labyrinth barrier of the inner ear and propose a drug, SPT-2101, which is already being evaluated in clinical trials for the treatment of Ménière's disease.

The blood-labyrinth barrier (BLB) of the inner ear is a structure with selective permeability, similar to the blood-brain barrier of the brain, that lets oxygen and nutrients pass to the cochlea, but prevents the entry of harmful, toxic or infectious agents. The alteration of the permeability of the BLB is a poorly understood pathological mechanism, which has been associated with rare diseases such as Ménière's disease, as well as other forms of sensorineural hearing loss (autoimmune, infectious, noise-induced).

In this work, the Neuropathology of Hearing and Myelinopathies group and Pilar López-Larrubia of the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM) and the Centre for Biomedical Network Research on Rare Diseases (CIBERER) have delved into the molecular, cellular and functional bases of this process, using an animal model of hearing damage induced by bacterial lipopolysaccharide (LPS), a potent inducer of inflammation.In addition, the efficacy of a new formulation of dexamethasone for local application was evaluated. Non-invasive in vivo evaluation techniques, such as auditory brainstem evoked potentials (ABR) and magnetic resonance imaging with dynamic contrast (DCE-MRI) were used, as well as RT-qPCR, PCR arrays and stria vascularis whole mounts, among others.

“The results obtained show that LPS produces an alteration of the BLB permeability from the first hours after administration, and this was associated with changes in the expression of inflammation genes”, says Silvia Murillo-Cuesta, first author of this work. The PCR array determined that there are specific expression patterns, which change throughout the first 72 h. Some of the key genes validated by RT-qPCR include the LPS receptor Tlr2 and the Cd14 co-receptor, cytokines and pro-inflammatory receptors such as Il1b and ll1r1, and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. Intratympanic administration of dexamethasone formulated as SPT-2101 (Spiral Therapeutics) prevented alteration of BLB permeability and reduced hearing loss in rats receiving LPS. The effects were similar to the administration of repeated doses of systemic dexamethasone, avoiding side effects. At the molecular level, SPT-2101 modulated expression changes and markedly reduced the inflammatory process in the cochlea.

This work, entitled: "Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation", has been recently published in Translational Medicine Communications.

The image shows a plane montage of the vascular stria of the rat inner ear; basal situation on the left and after administration of bacterial lipopolysaccharide on the right.