“The CRISPR technique can now target messenger RNA [mRNA], which theoretically could solve a lot of our problems, but there are a lot of practical details that would have to be worked out, at least in the human ear,” said Lawrence R. Lustig, MD, Howard W. Smith Professor and chair of the department of otolaryngology–head and neck surgery at Columbia University College of Physicians and Surgeons in New York City. He noted, for example, that any treatment for hearing loss would have to be performed in the earliest stages of fetal development; once degenerative hearing loss begins, there is no way to reverse it.
Explore this issue:December 2017
To test the viability of early treatment, Dr. Lustig and his colleagues are using adeno-associate virus type 1 (AAV1) vectors very early in the mouse life cycle, day 1 after birth, “which actually translates into a human baby in utero,” he said. In one study, his team used gene replacement therapy to restore hearing in a mouse model by using the AAV1 to deliver vesicular glutamate transporter-3 (VGLUT3) cells into the cochlea of impaired mice. Within two weeks of AAV1-VGLUT3 delivery, the newborn mice had restoration of their auditory brainstem response and partial rescue of the startle response (Neuron. 2012;75:283–293).
Dr. Staecker also underscored the importance of early intervention. “CRISPR will probably have to [be applied to] dominant genes before you have complete degeneration of the hair cell in question,” he said, adding that better screening of patients also would be needed. “It is not enough just to say ,‘You have hearing loss’; we need to define what a patient has on a structural, physiologic, and molecular level,” he explained. “You want to know exactly what is wrong with the ear—whether the problem is in the stria vascularis, the hair cell, or the spiral ganglion—what are the genes involved. We will not be there tomorrow, but it will be much sooner than expected.”
Dr. Staecker was instrumental in developing the first clinical trial of human inner ear gene therapy, including evaluating the efficacy of inserting the Atoh1 gene to help regenerate vestibular hair cells (Laryngoscope. 2014;124:S1–S12). “The trial [yielded] information on how to access the ear, how to deliver treatments, what doses the human ear tolerates, and sets the stage for the more complicated therapies. If we think about gene editing or gene replacement, we may have to treat the patient for the duration of their life rather than a one-time short intervention. So we have to approach all of these things slowly.”
If we think about gene editing or gene replacement, we may have to treat the patient for the duration of their life rather than a one-time short intervention. So, we have to approach all of these things slowly. —Hinrich Staecker, MD, PhD
The CRISPR technique holds the promise of targeting specific mutations in the DNA strand without affecting normal cells. Studies in the mouse model have run into problems, however. “There always is a risk that the technique is not selective enough to prevent the snipping of ‘normal’ portions of the strand or, potentially worse, inserting cells in the wrong place. Other concerns occur when only some of the embryo cells are repaired, called mosaicism,” Dr. Welling noted. Even in the landmark Nature study, the reported success rate was 72.4%. Most scientists agree that before this technique could be used in viable human embryos, the success rate would have to be 100% in the mouse models and larger animal studies.