The dawn of the 21st century witnessed the success of the Human Genome Project, the quiver of the Braille glove and the ease of obtaining both an ancestry profile and a diagnosis for genetic disorders from a do-it-yourself at-home DNA test kit. Advancements in healthcare since then have been aplenty – with various new therapies revolutionizing oncological studies; a promising one being regenerative cell therapy.
Although cell therapy was first performed in 1958 when French oncologist Georges Mathe transplanted bone marrow stem cells after six nuclear researchers were accidentally exposed to radiation, research picked up pace in the 2000s with the development of induced pluripotent stem (iPS) cells by Japanese researcher Shinya Yamanaka in 2006.
These cells, which mimic transient embryonic stem cells, are derived from skin and blood cells that are reprogrammed into a pluripotent state, enabling them to be differentiated into any cell in the human body. The notion of utilizing these cells for therapeutic purposes was made a reality when iPSCs were used as a resource to create heart cells, to study cardiovascular behavior, which heralded the scope for regenerative medicine.
Furthermore, the use of stem cells to replace bone marrow cells after being destroyed by cancer or exposure to radiation for the treatment of cancer, as well as the potential for stem cells to transform into brain cells and regulate dopamine levels to relieve some of the motor symptoms of Parkinson’s disease – being investigated through ongoing clinical trials – has evidenced the competence of stem cells in therapeutic research for a range of disorders.
With the proven science that stem cells can replenish and potentially take the form of any type of cell in the body, by virtue, this raises the question: could stem cells be transformed into auditory sensory cells and treat hearing loss?
Affecting more than a billion people worldwide, with 430 million diagnosed with disabling hearing loss, according to data from the World Health Organization, hearing loss can be caused by natural factors including aging, chronic exposure to loud noises or drugs, and even genetic variations, and it ranges in degree from mild to profound.
While surgical procedures to treat abnormalities of the eardrum or the ossicles (bones of the ear) are now routine, the medical devices currently used to treat inner ear (cochlea) dysfunction, hearing aids and cochlear implants, while remarkable, never fully restore hearing even with the best outcomes. Moreover, implants can sometimes cause a loss of residual hearing and, although rare, can pose a risk of meningitis.
Rinri Therapeutics’ stem cell therapy for hearing loss
To expand treatment options and develop therapeutics for hearing loss, UK-based Rinri Therapeutics, a spinout of The University of Sheffield, has evolved a regenerative cell therapy pipeline.
Its lead product is Rincell-1, a first-of-its-kind inner ear cell therapy that hopes to recover sensorineural hearing loss, specifically hearing loss caused by damage to the auditory nerves in the cochlea.
Derived from embryonic stem cells, Rincell-1, is an auditory neuron progenitor cell line that can specifically differentiate into mature auditory neuron cells. These cells are delivered to the cochlea, where the remnants of the auditory nerves reside, then differentiate into auditory neurons and send out neurites to connect to the auditory hair cells and back towards the brain stem; reconnecting the circuitry within the inner ear.
According to Simon Chandler, CEO of Rinri Therapeutics, who oversees product development as well as raising funds for the biopharma’s pipeline, sensorineural hearing loss is, in essence, a cellular problem. As a result, he believes that the logical solution to restore hearing is to repair this cellular damage with functional cells.
“We are taking the approach of transplanting in cells that can become functional mature cells and restore the cytoarchitecture of the inner ear, and therefore, restore hearing,” said Chandler, who vouches for stem cell therapy as a viable treatment method for hearing loss.
Having raised £18.3 million ($22.5 million) in funds from venture capital funds and non-dilutive funding: notably, Boehringer Ingelheim Venture Fund, UCB Ventures and Innovate UK, the company’s lead product, Rincell-1, has successfully progressed through preclinical development and is looking towards first-in-human clinical trials. In its first trials, Rinri proposed to administer Rincell-1 in combination with cochlear implants – devices designed to bypass damaged hair cells and directly stimulate auditory neurons – to enable the recording of objective measures of cochlear function rather than rely on more subjective measures such as speech recognition.
“Clearly, we’ll look at word recognition outcomes as well, but we need objective measures because we’ll then see categorically, mechanistically, what effect our therapy has on cochlea’s function without the need for people to interpret words and sounds,” said Chandler.
Chandler also said that as cochlear implants rely on auditory neurons to function, “there is a potential synergy” for Rincell-1 to be delivered alongside cochlear implants, “as there is the potential for Rincell-1 to improve the performance of cochlear implants by enhancing the number of neurons in the cochlea.”
However, it is important to stress that this does not rule out the possibility for stem cell therapy to function as a monotherapy for hearing loss in the future.
As most people will have lost a significant number of auditory neurons by the time they hit 60, with, on average, 50% of the auditory neurons lost or damaged in some cases, delivering cells that can differentiate into functional auditory neurons within the cochlea to restore hearing to a higher level of function could reduce the need for medical devices, according to Chandler.
Stem cell therapy for hearing loss: the challenges
Despite the potential, candidate cell therapies leading to clinical trials have not yet materialized, owing to the intricate nature of hearing anatomy and hearing disorders.
Moreover, the landscape for biopharmas in hearing loss therapeutic development has been challenging. Like, for example, Massachusetts-based Frequency Therapeutics, which recently laid off 55% of staff following a high-profile failed phase IIb study of its lead candidate FX-322. The company’s technology was based on regenerating auditory hair cells through the in situ trans-differentiation of residual cochlear cells. Although its safety profile was deemed favorable, the lack of improvements in efficacy resulted in the development of FX-322 being discontinued.
“Failure is not necessarily always due to lack of efficacy, but because hearing loss has until recently been a very challenging condition to perform clinical trials on because of the way you measure function. There are no biomarkers of hearing loss, you can’t do a blood test and see whether you have hearing loss and establish the underlying etiology,” said Chandler, who thinks that Rinri’s approach to clinical trials will overcome these challenges.
“Traditionally, you use subjective measures, like speech recognition, and they can be quite subjective depending on the audiologist taking those measures, which makes them quite noisy to use as outcome measures.”
While Frequency Therapeutics was unable to progress with clinical studies, Lineage Cell Therapeutics is currently conducting preclinical trials of ANP1, an auditory neuronal cell therapy program for the treatment of hearing loss.
Headquartered in California, the company’s technology is anticipated to illustrate its efficacy during preclinical trials, but only time will tell.
Yehoash Raphael, who is collaborating with Lineage on hearing loss research, said: “Despite extensive efforts using traditional molecular approaches or more recently, gene therapy, there still are no FDA-approved pharmacological options for these patients. ANP1 takes a different approach: it targets the auditory nerve with an allogeneic population of replacement cells to replace the missing auditory neurons. This offers a novel and potentially more clinically measurable effect than narrow and targeted methods. Rather than changing just one gene or one pathway, replacing the entire cell may be more broadly applicable across a large number of patients.”
While hearing loss cell therapy studies are nowhere near the finish line in order to review commercialization, uncertainty regarding affordability looms.
However, Chandler is optimistic. Since there are only 30,000 to 50,000 auditory neurons in the cochlea, and Rinri has a scalable manufacturing process, the treatment is unlikely to cost as much as CAR-T cell therapy or proposed regenerative cell treatments for more complex organs such as the liver.
Chandler said: “We also recognize that hearing loss is a global problem that is not restricted to high income countries or those with the means to afford expensive therapies. Our vision is to develop a therapy with a wide accessibility. Costs will start high, but as with all new technologies, like electric cars for instance, they start off at a high level but as production scales increase and achieve economies of scale, prices come down. We are in the early stages of ATMPs in healthcare and as manufacturing technologies improve, I can see the same happening for cell therapies.”
As Rinri Therapeutics prepares to begin clinical trials for Rincell-1 in 2024, Rincell-2 (auditory neuron progenitors derived from iPS cells) and Rincell-3 (auditory hair cell progenitors) are being developed as part of the pipeline.
Despite the many challenges that come with the development of regenerative medicine for the treatment of hearing disorders and more that await, with the progress in current therapeutic research and potentially successful clinical trials in the future, there could be a light at the end of the tunnel to possibly reverse sensorineural hearing loss.
“It is well recognized that hearing loss significantly impacts quality of life, affecting individuals through to economies. A biological solution that can restore hearing to a significant level is potentially transformative to patients,” said Chandler.