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1-Vektor Otoferlin DFNB9 Gentherapie

Ref-Nr: TA-MBM-BioT-2085-UMG


Kurzfassung

Bis jetzt war ein Ein-Vektor vermitteltes Einbringen des OTOF Genes durch seine Größe eine Herausforderung. Angebot: ein 1-Virus-System vermitteltes Einbringen und Expression der vollständigen Otoferlin-Sequenz in die Gehörschnecke zur Wiederherstellung des DFNB9 Hörvermögens durch Mutationen im Otoferlin Gen. 


Hintergrund

Mutations affecting the OTOF gene lead to severe non-syndromic form of prelingual or temperature-sensitive hearing impairment DFNB9. Due to the large OTOF size a one-vector delivery has remained challenging.
The technology offered: Gene-therapy of the otoferlin gene (OTOF) with overloaded AAV virus mediated one-vector delivery of full-lenght otoferlin or active fragment thereof into the cochlea. In vivo proof-of-concept successfully achieved. We filed international IP rights and are looking for a licensing partner to develop and market a product.


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Problemstellung

Deafness challenge: Molecular diagnostics have identified novel deafness genes, but no causal treatments are clinically available. The sole therapeutic option is the earliest possible fitting with hearing aids or cochlear implants. Gene therapy is emerging as a promising tool to correct faulty gene expression.

Otoferlin vs. deafness: Mutations affecting the OTOF gene lead to severe non-syndromic form of prelingual or temperature-sensitive hearing impairment DFNB9. OTOF-related deafness accounts for up to 8% of autosomal recessive non-syndromic hearing loss in some Western populations. OTOF-related deafness resides within the top five of genetic hearing disorders that still require therapeutic intervention.

Otoferlin challenge: It is abundantly expressed in sensory inner hair cells (IHCs) of the cochlea. It serves as a key role in the final steps of synaptic vesicle fusion at cochlear hair cell synapses with afferent spiral ganglion neurons. To date, several OTOF mutants are known. Otoferlin deletion mice mutants are completely deaf. Due to the large OTOF coding sequence (5991 kb) and the restricted packaging size of standard adeno-associated viral vectors (AAV, <4.4 kb) that are commonly employed for gene therapeutic applications based on their favorable safety profile, the delivery of the large full-length OTOF gene has remained challenging.


Lösung

We offer: an overloaded AAV virus one-vector delivery of full lenght otoferlin (or active fragments thereof) into the cochlea for treating OTOF related deafness. We achieved a successful in vivo proof of principle showing hearing rescue. Thus, Otoferlin genetic rescue is indeed feasible and exerts clinical potential.

Recently new capsid designs have been developed to carry larger genes. The innovative construct is using an AAV/PHP.B vector carrying the full-length otoferlin-cDNA under the control of the CAG-promoter.

 

Highlights: Injection into the cochlea of early postnatal mice (p5-7). The transduction of otoferlin knock-out mice (Otof-KO) with the innovative construct achieved:

  • Clinically relevant transduction rates of IHCs.
  • Produced adult animals with measurable auditory brainstem response thresholds.
  • No side-effects did appear.
  • The innovative construct might form a solid basis for the further development of gene replacement therapy for DFNB9 patients.

Vorteile

  • One-vector system for Otoferlin based gene therapy.
  • Simpler to be produced by companies.
  • Easy to be used for patients and easyly administered by doctors.
  • Easy to be received by patients.

Anwendungsbereiche

For restoration of hearing in deafness DFNB9 patients (with any mutation/s in the otoferlin gene).


MBM ScienceBridge GmbH

Dr. Stefan Uhle
0551-30724 154
suhle@sciencebridge.de
www.sciencebridge.de
Adresse
Hans-Adolf-Krebs-Weg 1
37077 Göttingen



Entwicklungsstand

Präklinik


Stichworte

MBM ScienceBridge GmbH, Technologieangebot/technology offer, Technologietransfer/ technology transfer, Georg-August-Universität Göttingen/ oder anderer Verbundspartner, tobias moser, universitätsmedizin göttingen, mbm sciencebridge, auditorische neurowissenschaften, otof, otoferlin dfnb9, schwerhörigkeit, gentherapie, überbeladener AAV,

Angebot Anbieter-Website


Kontakt | Geschäftsstelle

TechnologieAllianz e. V.
Christiane Bach-Kaienburg
(Geschäftsstellenleiterin)

c/o PROvendis GmbH
Schloßstr. 11-15
D-45468 Mülheim an der Ruhr