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A new study demonstrated the effectiveness of gene therapy in the recovery of hearing for those suffering from hereditary deafness called DFNB9, a significant concern given more than 1.5 billion people are affected by hearing loss worldwide. Out of these, about 26 million are suffering from congenital deafness, which is hearing loss present at birth.
Moreover, in humans, sensorineural (hearing loss due to damage to the inner ear) hearing loss is one of the most common sensory deficits in humans. In developed countries, this type of hearing loss affects one to two per 1000 newborns.
The first deafness gene was discovered over the past few decades, and since then, over 120 genes have been associated with causing non-syndromic hearing loss, which is a partial or total loss of hearing that is not associated with other signs and symptoms.
Now, DFNB9 or autosomal recessive deafness 9 (DFNB9) is characterized by two major features: bilateral nonsyndromic hearing loss before the individual has developed the use of language and the less common temperature-sensitive nonsyndromic auditory neuropathy.
This inherited deafness usually happens during the first two years of life as an auditory neuropathy. This disability is caused by pathogenic sequence variants in the otoferlin (OTOF) gene, which is 21 kb in size. It is mainly expressed in the inner hair cells of the cochlea and the brain and may be involved in synaptic vesicle trafficking. Mutations in this (Otoferlin) gene cause DFNB9.
Now, to treat this disability, researchers from Mass Eye and Ear conducted a new study. A member of Mass General Brigham, Mass Eye, and Ear is a Boston-based specialty hospital that focuses on ophthalmology (eye care), otolaryngology (nose, ear, and throat care), and related medicine and research. This international center was founded in 1824 and is a teaching hospital of Harvard Medical School.
The specialist teaching hospital began the clinical trial more than a year ago as the first to make use of gene therapy on a child with DFNB9. It also has the highest number of patients treated and has the longest follow-up to date.
The trial was in collaboration with the Eye & ENT Hospital of Fudan University (FDEENT) in Shanghai, China. The trial took place in China, and it reported that five of the six children treated with gene therapy showed hearing recovery and improvements in speech recognition. As per the results, which were published in The Lancet on January 24th and will also be presented later this week at the annual meeting of the Association for Research in Otolaryngology, the study reported no dose-limiting toxicities.
Currently, there are no drugs approved by the US Food and Drug Administration (FDA) to help with hereditary deafness, leading to the discovery of new solutions like gene therapies. And the novel technology is found to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9.
A Look at Gene Therapy
Before we take a deeper dive into the outcomes of the study, let's first take a look at gene therapy. This type of disease treatment alters the genes inside the body cells, either replacing a faulty gene or adding a new one to cure or combat diseases more effectively.
Genes contain DNA (Deoxyribonucleic acid), which is a molecule that carries all the information for the development and functioning of an organism. When they don't work properly, they cause disease. In gene therapy, the approach might involve replacing the faulty gene or adding a new gene to cure the disease or help the body fight the disease better.
Researchers are investigating to replace the mutated genes because they work incorrectly or don't work at all. For instance, many cancer types have been linked to a defective p53 gene as it prevents tumor growth. So, by replacing this faulty gene, cancer cells can be triggered to die.
Another way is to fix mutated genes that are causing diseases in an individual. If doctors turn off the particularly responsible gene, it will stop promoting the disease. The immune system could also be trained to recognize diseased cells and then attack them.
This way, gene therapy holds great potential to treat many diseases, such as heart disease, diabetes, cancer, cystic fibrosis, hemophilia, and AIDS.
However, it is not as widely used. For instance, in the US, it is currently only available as part of clinical trials, which are monitored by the FDA and the National Institutes of Health (NIH). Researchers around the world are still studying how to safely use gene therapy and its impact.
When it comes to the method used to transfer genetic material into cells, there are two types: viral and non-viral vectors.
Viral vectors, which achieved clinical success in the early 90s, have been used for both acute and chronic diseases. These vectors can be optimized to allow for the specific targeting of tissues, chromosomal integration at a particular location, and efficient infection of the dividing and non-dividing cells in the long term.
In contrast, non-viral gene delivery methods use natural compounds and are relatively safe. They also have low immunogenicity, which is the ability of an antigen to trigger immune responses from the body. They further benefit from the lack of DNA insert size limitation but are restricted by low gene transfer efficiency.
While gene therapy is extremely beneficial, it isn't without issues. Because gene therapy involves using a vector as a carrier, the body may recognize the newly introduced carrier (like viruses) as an intruder and attack it, causing inflammation and even organ failure.
There's also the possibility of unintended gene editing. This off-targeting can cause serious health issues such as cancer.
The high cost of gene therapy is another big downside, as the cost of this treatment can easily run north to millions of dollars. As such, not many people can afford it. Gene therapy companies, however, justify the price tag by citing the considerable improvement in the quality of life that this novel treatment offers. That said, the costs are expected to come down once products are developed for more prevalent diseases with larger patient populations.
Over the years, gene therapy has helped babies born with retinal diseases that have led to total blindness, programmed immune cells to recognize and target cells with cancerous mutations, and has allowed for treating blood disorders like sickle cell disease and beta-thalassemia via precision editing. Gene therapy has also been showing promising results in derailing a potentially lethal neurodegenerative disease like spinal muscular atrophy (SMA) by delivering required genetic instructions directly to cells in the body.
So, by manipulating a gene's expression or modifying the biological properties of living cells, gene therapy continues to show great potential and be an active area of research to develop new, effective treatments for a variety of diseases.
“Truly Remarkable” Results of the Study
Now, back to the study conducted by the US-based Mass Eye and Ear and China-based Eye & ENT Hospital of Fudan University, which was funded by the Shanghai Refreshgene Therapeutics, National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality.
In children born with hearing loss, 50% to 60% of the disability is due to genetics. DFNB9 is an example of that, a genetic disease caused by the OTOF gene's mutation. This disease is caused by a failure to produce a functioning otoferlin protein because otoferlin protein is necessary for the transmission of sound signals from the ear to the brain.
According to Zheng-Yi Chen, DPhil, an associate scientist at Mass Eye and Ear's Eaton-Peabody Laboratories (EPL), the inability of children to hear can lead to abnormal brain development without intervention.
This AAV, capable of being engineered to perform specific functions in gene therapy, has been demonstrated to be both effective and safe in clinical trials.
The AAV carried a version of the human OTOF gene, which the researchers introduced into the inner ears of the patients through a specialized surgical procedure using a single injection of the viral vector at varying doses.
All the children in the trial had total deafness, with an average auditory brainstem response (ABR) threshold of over 95 decibels. However, after 26 weeks, five out of six children showed significant hearing recovery, evidenced by a 40-57 decibel reduction in their ABR testing. Additionally, there were marked improvements in their speech perception, and their ability to engage in normal conversations was effectively restored.
“The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”
– Chen, who's also an associate professor of Otolaryngology at Harvard Medical School
As for any signs of severe toxicities during the therapy, no dose-limiting toxicity was observed. However, a follow-up on the patient revealed 48 adverse events. The majority of these events (96%) were low-grade, while the rest were temporary with no long-term impact.
This study, which is the first one to initiate the clinical trial of OTOF gene therapy, truly demonstrates the effectiveness of gene therapy as well as evidence of its safe usage in treating DFNB9. But this is not all. This treatment also has the potential for other forms of genetic hearing loss.
“I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”
– Yilai Shu, who's the lead author of the study
Shu is the deputy director of the FDEENT and, before that, served as a postdoctoral fellow in Chen's lab at Mass Eye and Ear.
Besides showing the promise of gene therapy in hearing loss, the study also contributes to an understanding of the safety of AAV insertion into the human inner ear. Generally, AAVs have a gene size limit, but in this case, a dual-AAV vector successfully carrying two pieces of the OTOF gene is notable, opening the door for its use with other large genes that may be too big for the vector.
In the next step, the researchers plan to expand the clinical trial's sample size and track their results over a longer timeline. Chen said:
“Not since cochlear implants were invented 60 years ago has there been an effective treatment for deafness. This is a huge milestone that symbolizes a new era in the fight against all types of hearing loss.”
Companies Using Gene Therapy to Develop Solutions
Now, let's take a look at a few prominent names using this novel technology to develop solutions to human impairments, including prosthetics, hearing loss, sight loss, and more.
Acquired by the Swiss pharmaceutical giant Roche in 2019 for $4.8bln, Spark Therapeutics is known for receiving the first FDA approval for treating hereditary retinal disorders in 2017. The solution was Luxturna, a gene therapy for a rare form of inherited blindness. While a costly treatment, over 300 eyes have been treated with it, and it continues to show incredible results, with patients retaining their improved vision several years later.
Spun off from Children's Hospital of Philadelphia over a decade ago, Spark is now focusing on a new product line to bring gene therapies to diseases that afflict much larger patient populations. Last year, the company broke ground on its biggest project to date, a $575 million gene therapy innovation center in Philadelphia. Spark's second product in the market could be an experimental hemophilia B treatment that it licensed to Pfizer in 2014. Meanwhile, the company's hemophilia A gene therapy candidate is in phase 3 clinical testing, and another one for Pompe disease is in the early stage.
#2. Editas Medicine
This company is leveraging gene therapy for people with serious diseases. Editas Medicine is working with the Cas9 and Cas12a CRISPR nucleases, which give access to a variety of genetic mutations. Recently, the company shared early data for its gene-edited candidate renizgamglogene autogedtemcel (reni-cel), designed to tackle sickle cell disease (SCD). Last month, Vertex Pharmaceuticals signed a $100 mln license agreement with Editas to use its Cas9 gene editing technology.
The genome editing company's shares are currently trading at $7.63, down 24.68% year-to-date (YTD). Editas posted revenue training for twelve months (TTM) of $24.61mln and has an EPS (TTM) of -2.71 and a P/E (TTM) of -2.82.
This one specializes in AAV vector engineering and develops next-generation AAV capsids for gene therapies. Earlier this year, Novartis signed a collaboration and capsid license agreement worth $1.3 bln with Voyager to develop gene therapies for Huntington's disease and SMA.
With a market cap of $409.825 mln, Voyager shares are trading at 7.60, down 9.95% YTD. The company posted a revenue (TTM) of $158.39mln and has an EPS (TTM) of 1.24 and a P/E (TTM) of 6.11.
Gene therapy is the top pharmaceutical trend, and for good reason. The ever-evolving field is becoming an important focus within the healthcare industry for its ability to treat conditions like hearing loss by editing the mutations that cause them.
While there are several challenges to be addressed, as the field of gene therapy continues to expand, we will have life-changing treatments that were previously not possible to change the healthcare sector completely.