Sirna Therapeutics said this week that it has formed a sponsored-research collaboration with Massachusetts General Hospital researcher Zheng-Yi Chen to support his work into using RNA interference to restore hearing loss.
Chen's research focuses on the gene expressing retinoblastoma protein, pRb. According to Chen, this gene has been found to play a role in the production of hair cells in the inner ear, which convert sound into neural impulses.
"Those cells are equivalent to photoreceptors in the retina," he told RNAi News this week. "They basically perform a role in signal transduction, converting mechanical stimuli into electric signals."
Chen noted that the loss of these cells, which don't regenerate in mammals, is closely associated with hearing loss, regardless of its origin. "If you don't have hair cells, you don't hear …and the loss of hair cells is the primary reason for … pretty much [all] kinds of hearing loss," he said. Hearing loss could be a result of "noise, it could be drug-related — if you look at all [causes], they all have hair cell loss as a hallmark.
"We're born with about 37,000 of these hair cells, and that's all we have for the rest of our lives," Chen noted. "If we lose one, we lose it permanently." He added that when compared with the millions of photoreceptors in the eye, the loss of even a small number of hair cells is very significant.
Chen said that microarray analysis of all the genes involved in inner ear development revealed that pRb, which is expressed by multiple cells, is strongly expressed by hair cells. Additional work in mouse models showed that blocking the production of this protein allows hair cells to regenerate. This work was described in a paper by Chen and his colleagues published in the February 18 issue of Science.
"If the gene is expressed normally, you just get a finite number of cells," he said. "However, if you take out the gene or inhibit its function, the cells somehow keep dividing, and those newly derived cells somehow become" mature, functional hair cells.
Chen noted that RNAi offers an optimal approach for down-regulating pRb because retinoblastoma is also a tumor-suppressor gene, and permanent knockdown could have deleterious effects.
While the gene's role in the ear seems linked just to hair cell development, "in the eye, if this gene is mutated or patients don't have it, they develop tumors," he said. "So we really don't want to take out the gene permanently because we don't know what the long-term consequences could be. What we want to do is inhibit the function of [the gene] very briefly … because all we need really is just to get the cells to divide once or twice to have all the cells [needed] to hopefully restore hearing."
According to Chen, Sirna is providing his lab with an undisclosed amount of funding to continue his work on hair cells, as well as its RNAi expertise in areas including siRNA modifications. He added that the company has expressed interest in possibly licensing the technology at a later date. Additional terms of the arrangement were not disclosed.
"Academic research collaborations, such as this, are an important part of Sirna's mission to advance our understanding of the biological relevance of RNAi and development of siRNAs as potential therapeutics," Roberto Guerciolini, Sirna's chief medical officer, said in a statement. "If the research we are supporting demonstrates that the temporary knockdown of the retinoblastoma protein in mice will result in regeneration and functional differentiation of hair cells, it will open the opportunity for the therapeutic application of siRNAs for the treatment of hearing loss related to hair cell destruction."
Rebecca Robison, senior director of corporate strategy at Sirna, declined to comment on the market potential for a hearing restoration drug, stating that the company is at "such an early stage in the collaboration [and] … we're a long way away from bringing [a drug] to market." However, Chen noted that between 28 million to 30 million people suffer from some level of hearing loss in the US alone.
Robison also declined to comment on whether the hearing restoration program was one Sirna would consider developing on its own.
The company recently announced that it was narrowing the focus of its pipeline to its age-related macular degeneration, hepatitis C, and permanent hair-removal programs in an effort to curb costs (see RNAi News, 5/13/2005). Sirna also said that its other programs, all preclinical, would be "advanced with a combination of internal and external support."
"We're certainly not at that stage" where a decision on development for a potential hearing restoration therapy would be made, she told RNAi News this week, adding that a development timeline was not publicly available either. "At this point, this is an academic collaboration, so it's not part of our pipeline just yet."
Prior to refocusing its pipeline, Sirna provided estimated timelines for all of its drug-development efforts. Now it seems Sirna has taken a page out of rival Alnylam Pharmaceuticals' playbook by only providing details on its lead programs, and not even including its earliest-stage efforts in its formal pipeline.
"We're talking about our core [projects] most specifically because those are the programs that are the furthest developed," Robison said. "To give timelines for those, we can certainly be far more accurate than with earlier-stage programs where timelines can shift and move. We're just trying to be very accurate and give a very cohesive message to the marketplace."
— Doug Macron ([email protected])