All Eyes and Ears for Gene Therapy
Authors: Seppo Ylä-Herttuala
Journal: Molecular Therapy (2018)

During the last year, we have witnessed many successful clinical developments in gene therapy. Following the recent success of CAR-T-based clinical products, gene therapy has entered the field of ophthalmology with the December 2017 approval of Luxturna for the treatment of retinal dystrophy.1U.S. Food and Drug Administration. (2018). FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss: Luxturna is the first gene therapy approved in the U.S. to target a disease caused by mutations in a specific gene. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm589467.htm.Google Scholar This adeno-associated virus (AAV)-based therapy delivered by subretinal injection has since been administered to a few patients. Several other applications are currently under development for various types of severe eye diseases, including retinitis pigmentosa and wet macular degeneration, which affects a large number of the elderly worldwide. It is expected that several significant advances will be made in the next few years in the clinical applications of gene therapy in ophthalmology. The ear is another sensory organ that offers a good target for gene therapy. The inner ear and organ of Corti are easily accessible to targeted injections of vectors, and there are several inherited and acquired conditions that destroy inner ear cell function and lead to hearing loss. If defective cell function could be restored even partially, this could help a significant number of those affected. Already a decade ago, improvement in hearing was achieved with Atoh1 gene therapy in deaf guinea pigs, with cellular and functional restoration of the damaged sensory system.2Izumikawa M. Minoda R. Kawamoto K. Abrashkin K.A. Swiderski D.L. Dolan D.F. Brough D.E. Raphael Y. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.Nat. Med. 2005; 11: 271-276Crossref PubMed Scopus (564) Google Scholar In addition, gene transfer of vascular endothelial growth factor into the inner ear has been attempted for the restoration of dysfunctional hair cell function, but no clinical trials have yet been initiated. At the 2018 annual meeting of the American Society of Gene and Cell Therapy (ASGCT), several presentations showed progress in preclinical development of gene therapy for ear diseases. One well-known condition is Usher syndrome type IIIa, which is a recessive disease caused by a mutation in CLRN1 gene, leading to progressive hearing loss and retinal degeneration. Mouse models are available for this disease, and AAV9-CLRN1 gene transfer has been shown to rescue hearing loss in neonatal mice, at least at lower frequencies. Another mouse model successfully treated is the so-called Beethoven mouse, which loses hearing early in life owing to a defect in the Tmc1 gene, which leads to destruction of the inner hair cells. In this case, CRISPR/Cas9 technology was delivered by AAV vectors for targeted gene editing, resulting in improved hearing and function of the inner ear hair cells. Olfactory gliopathy is another example of a disease where intranasal gene transfer, in this case with an adenoviral vector, encoding IFT88 has restored cilial cell function and improved odor detection, which led to behavioral changes in a mouse model of the disease. Hearing problems are commonly caused not only by genetic defects and aging but also by ototoxic drugs, infections, and exposure to excessive noise. Therefore, applications toward treatment of these problems could have a significant positive effect on the quality of life of individuals affected by these conditions. In this issue of Molecular Therapy, a further application of gene therapy to ear diseases is described by Duarte et al.3Duarte M.J. Kanumuri V.V. Landegger L.D. Tarabichi O. Sinha S. Meng X. Hight A.E. Kozin E.D. Stankovic K.M. Brown M.C. Lee D.J. Ancestral Adeno-Associated Virus Vector Delivery of Opsins to Spiral Ganglion Neurons: Implications for an Optogenetic Cochlear Implant.Mol. Ther. 2018; 26 (this issue): 1931-1939Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar They take an optogenetic approach where genes encoding light-sensitive proteins, known as opsins, were transduced into cochlear spiral ganglion neurons via the round window of the cochlea in neonatal mice. The authors used an AAV vector termed Anc80L65, which has higher transduction efficiency and stability compared to previous AAV vectors in a number of systems, including cochlear hair cells. By giving pulsed blue light to the cochlea via a cochleosotomy using a flexible optical fiber, they were able to show light-induced gene expression and optically evoked auditory electrophysiological responses. Results may lead to a new generation of cochlear implants based on light activation. The studies described above are examples of the versatile nature of gene therapy in eye and ear diseases. With improved vectors and local gene transfer techniques, it is expected that several diseases in these organs will be treated with gene therapy to recover at least partial sensory functions and to improve the quality of life of the patients. Ancestral Adeno-Associated Virus Vector Delivery of Opsins to Spiral Ganglion Neurons: Implications for Optogenetic Cochlear ImplantsDuarte et al.Molecular TherapyJuly 13, 2018In BriefDuarte et al. describe the novel pairing of a synthetic viral vector with optogenetics to target spiral ganglion neurons of the cochlea, a first step toward a light-based cochlear implant. They successfully introduce the Chronos opsin to the complete cochlear axis of mice, generating broad auditory responses upon light stimulation. Full-Text PDF Open Archive