February 6, 2017

expert reaction to two papers on gene therapy for deafness in mice

Two papers publishing in Nature Biotechnology have reported – in a mouse model of Usher syndrome – the efficient delivery of genes to the inner ear, which led to an unprecedented correction of hearing loss and balance symptoms.

Prof. Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

“Given that around 50% of people who have hearing problems have a genetic mutation as a cause of their disease, then using a gene based therapy to treat it is a logical solution. However although many approaches have been made to develop a gene therapy to treat hearing loss over the past several years, most have failed and only one using an adenoviral vector has progressed into humans. The main reason for the lack of progress being that the gene therapy is unable to reach both the inner and outer cells within the ear that are essential for correcting the hearing defect. What these two papers have demonstrated is that by developing a totally new synthetic adeno-associated viral (AAV) vector that carries the gene therapy and using it in a mouse model of deafness that is caused by a genetic mutation, that it is possible to reach both the inner and outer cells in the ear and correct not only the hearing problems but also the balance problems that these mice had.

“This is a very encouraging result particularly as this treatment has been shown to improve both hearing and balance aspects of the disease, but it is only in a mouse model. One of the biggest risks is that the new synthetic viral vector has not been given to humans yet. Although AAV vectors, which were the template for this new vector, have been used extensively in humans to date and also forms the basis of an already approved product for another disease, it is not known how humans may react to this new vector from an immunological standpoint and this needs to be investigated fully. Much more work needs to be done before it could be given to a patient and that’s at least three years away, if not more.”

Prof. Jonathan Ashmore, Bernard Katz Professor of Biophysics, UCL Ear Institute, UCL, said:

“These two papers, although connected as they come from the same laboratory at Harvard, are distinct.  The first* is about an interesting improvement in virus technology for gene therapy, originally developed to treat disorders in the retina, but now shown to be usable in the (mouse) ear without apparently affecting normal hearing.  The second^‡ is the application of the same technology, not just with the new virus but with some of the old ones as well, to fix a particular form of hereditary deafness.  Although there have been other papers on this topic published recently, these two new studies are very thorough  – they have done all the most obvious tests – although they are restricted to treating gene deficient mouse models of hereditary deafness. There are some caveats though. The virus has to be delivered in a very narrow window of time when the cochlea is still developing. Therefore we are still quite a way from treating human disorders, as the translation of this treatment would be to the cochlea in utero. The first paper* from Stankovic et al does provide some evidence that cells in the adult human balance system can be transfected with the new virus.  There is currently a limit on the size of the gene which works with this virus, so not all genes can be delivered and not all forms of deafness can be treated.

“The questions are whether such treatments could work clinically for humans when the ear has already formed – and whether the gene delivery can be restricted to the inner ear alone. There is some evidence the current adenoviruses ‘leak’ to transfect the cerebellum as well so ways of controlling the virus target needs attention. But there is clearly incremental progress and really good high quality laboratories are interested in the problem.”

* ‘A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear’ by Landegger et al. & ^‡ ‘Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c’ by Pan et al. published in Nature Biotechnology on Monday 6th February.

Declared interests

Prof. Alan Boyd:  Paid employment or self-employment – Director of Boyd Consultants which helps Universities and small companies develop their research ideas into medicines for use in patients. Voluntary appointments – President of FPM & Honorary Professor, University of Birmingham, Medical School.

Prof. Jonathan Ashmore: Has no conflicts of interest but does work at the same institute, UCL Ear Institute, as some of the authors.