Gene therapy, by which specific sequences of DNA are used to treat human disease, is in its infancy as a clinical treatment but has a unique application for hearing loss.
Relevant to our field, a single gene called atonal homolog-1 (Atoh1 or Math1) causes cochlear supporting cells to develop into functioning hair cells and may eventually be used as a hearing loss treatment.
In fact, the therapeutic use of Atoh1 to restore sensorineural hearing loss is currently being investigated in many laboratories and private biotechnology companies. Novartis has invested about $500 million and created a new division aimed at developing the first generation of Atoh1 therapies.
However, the current technological limitations of gene therapy, such as the inability to target gene delivery to specific cell types and the lack of appropriate control over the levels of gene expression, must be addressed before moving these technologies forward.
The latter problem is significant because current technologies result in little to no control over the concentrations at which a gene is expressed once it is introduced into the host tissue—a major impediment to clinical safety.
An Independent Construct for Conditional Expression of Atonal Homolog-1
Parker MA, Cheng YF, Kinouchi H, Bieber R, Edge AS
Human Gene Ther Methods
My laboratory recently published a paper describing a way to modify the Atoh1 gene to allow a controlled amount of expression, which may help move this therapy closer to clinical use.
The approach uses a helper gene—the ligand-binding domain of the human estrogen receptor—to regulate the levels of Atoh1 expression in host cells. In this system, cells express an inactive form of Atoh1 and function normally.
However, the drug tamoxifen can activate and deactivate Atoh1 in a tightly regulated manner. The dose of the drug can be changed to adjust the level of Atoh1 gene expression.
The system is analogous to the use of a light dimmer switch versus a spotlight. Standard gene therapies turn on genes at maximum levels, similar to a spotlight that is switched on constantly until it burns out completely.
However, our system allows for tamoxifen-dependent expression of Atoh1, similar to a dimmer switch that can be turned up as bright as a spotlight, turned down, or even turned off completely.
The long-term objective of this system is to produce a tightly regulated gene therapy for hearing loss. In this hearing therapy, a surgeon would inject the inactive form of Atoh1 into the cochleas of people with hearing loss, and the inner ear cells infected with this transgene would function normally.
The person would take an oral dose of tamoxifen to activate Atoh1 signaling in infected cells. The infected cochlear-supporting cells would then regenerate into functioning auditory hair cells, with hearing restored in a matter of days. The person would stop taking tamoxifen to deactivate Atoh1 signaling.
To date, this independent and inducible system has only been tested in isolated cells and organ of Corti explant cultures in laboratory experiments.
Therefore, future goals focus on overcoming the major technical hurdles of delivering this construct to the appropriate cell types in the organ of Corti and measuring the approach's effectiveness in animal models, leading to clinical trials.