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Concept and objectives of the AFHELO research program.



The sense of hearing is dependent of the integrity of the sensory epithelia in the inner ear. HI occurs when this tissue is disrupted.

Hearing deficits are generally associated with the loss of the sensory “hair” cells and/or neurons due to genetic defects or to external factors, such as ototoxic damage, noise trauma or ageing.

Sensorineural hearing impairment (HI), which affects both the sensory epithelia and the neurons in the cochlea, is a clinical heterogeneous disorder with a high prevalence and currently the only available treatment is limited to hearing aids and cochlear implants.

Studies are being conducted to develop alternative treatments combining both preventive and reparative strategies.

Lots of preventive strategies were developed around the use of antioxydants to limit cell death induced by oxidative stress.

For treatment approaches, the most developed is the use of growth factors (especially brain and glial‐cell‐line‐derived neurotrophic factors and neurotrophin‐3). These proteins activate growth, proliferation and differentiation of neuron precursors through binding to membrane receptors, and were showed to be candidates for treatment of HI.

Despite of the promising results in animal models, these factors were not very potent in the clinic and showed secondary effects including neuropathic pain in certain contexts. Therefore, new therapeutic approaches must be developed to answer this unmet medical need.


Affichem (coordinator - partner 1) is a spin‐off of the INSERM, French institute of health, focused on developing small molecules, named Dendrogenins, a class of alkylaminooxysterols, which are strong inducers of cell differentiation. Among these, AF243 showed interesting potencies of carcino‐embryonic cells differentiation and neuron survival. These effects led Affichem to evaluate AF243 potency on an in vivo model of chemo-induced deafness, used for cochlear implant testing, during FP6 Eurohear project. The results were of valuable interest since a patent and a scientific manuscript are pending.

Altogether these results prompted us to investigate AF243 potency on other causes of HI.


The strategy of AFHELO project is to optimize AF243 development by first extending the therapeutic applications to two major types of HI and second by completing the preclinical studies (pharmacology, mechanism of action, ADME, safety) supporting the clinical evaluation of AF243 for prevention and/or treatment of sensorineural HI. For this purpose, investigations will be focused on two main domains:

   - Definition of the pharmacology, the mechanism of action and the target(s) of AF243. These data will support the potential of development of the molecule, i.e. validate the therapeutic/preventive potential, the therapeutic window and the safety profile and discovery of biomarkers. All these data being necessary for the definition of the clinical pathway.

   - Validation of the potency of the drug in vivo on relevant models. Pre‐clinical validation on such robust animal models is a prerequisite for clinical trials.

 

Moreover, the experimental knowledge and technical know‐how accumulated during this project will be efficient tools for future evaluation of the potency of new drug candidates.

 

Finally, partner 2 (GIGA) and partner 3 (CSIC) work in close collaboration with clinical center specialized in sensorineural HI and AFHELO project will benefit of the clinicians point of view to orient this translational research to address actual needs of patients.


Therefore, AFHELO includes direct studies of the potency of AF243 use for prevention and/or treatment of sensorineural HI in humans, which is to date an unmet medical need and development of knowledge and know‐how that will be suitable for other studies.


Altogether these statements fit with the European Innovation Partnership “Active and Healthy Ageing” objective of increasing the average number of healthy life years by two for European people in 2020.



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