Gene therapy is a biotechnological achievement that represents one form of genetic modification in humans for health applications, a field that received a massive boost after the completion of the Human Genome Project in 2003. This technology addresses the root cause of genetic diseases by seeking to repair or replace defective genes, offering a personalized and potentially curative approach that is of considerable medical interest. One example of its application is the development of DB-OTO gene therapy in the CHORD clinical trial (NCT05788536). The aim of this registrational study was to treat congenital hearing loss in children caused by a mutation in the OTOF gene, promising natural hearing instead of the partial correction offered by cochlear implants. Although the trial has shown excellent preliminary results in pediatric participants, gene therapy as a whole faces significant challenges, such as its exorbitant cost, the complexity of the therapeutic products, and safety issues, requiring prior evaluation of its efficiency and safety by expert and bioethics committees before approval.
Applied genetic engineering aimed at modifying the genes or genomic regions involved in traits of interest of living beings began in the 1970s with two types of approaches. After the development of DNA isolation, cloning, and handling techniques, “transgenesis” emerged, aimed at transforming a recipient organism by adding genes from the same or different species to acquire a trait that it lacked. This resulted in multiple applications in microorganisms, plants, and animals. “Transgenic” and genetically modified organisms (GMOs) have enabled important advances in the field of health, such as the synthesis of human proteins and the production of pharmacologically relevant molecules in bacteria, plants, and animals. Building on this experience, in a second approach, genetic modifications in humans for health-related purposes emerged, a practice commonly known as “gene therapy”. This aspect received a huge boost in therapeutic, diagnostic, and pharmacological applications after the culmination of the Human Genome Project in 2003.
After identifying the gene or genes implicated in a genetic disease, the goal is to develop techniques to isolate and clone the corrective gene sequences and deliver them into the patients’ cells in order to repair or replace the defective genes, or to introduce new instructions to combat the genetic disorder. The corrective molecules are introduced into the recipient cells using unarmed viruses or other vectors such as nanoparticles, electroporation, etc. By addressing the root cause of the disease, gene therapy offers a personalized and potentially curative approach of considerable interest in healthcare.
Gene therapy gained momentum in the 1990s. Since then, preclinical trials have been conducted with animal models, followed by clinical trials in humans, making gene therapy a highly dynamic area of research.
There are two methods common to all types of gene therapy techniques: either ex vivo modification of the DNA of patient cells, with subsequent autotransplantation after confirming the desired change in the laboratory; or local or systemic in vivo delivery of the appropriate gene sequences or reagents to the target cells. These techniques are not a cause for ethical concern when applied to a patient’s somatic cells. However, their potential application in germline tissues raises ethical objections, since any unintended gene modification resulting from an error could affect the offspring.
The interest in gene therapy has been growing, and today this technology is being used to target many malignant disorders responsible for a wide range of diseases, such as cancer, hereditary diseases of blood, muscle, neural cells, etc. or to strengthen the immune system. As in all applications that carry some risk for patients, specific clinical trials must be carried out before their application; these must be previously submitted to expert and bioethics committees, where their efficiency and safety are evaluated. Many of the innovative treatments encounter significant challenges, such as high costs, the stability of the corrected DNA regions, collateral safety issues, complexity of the therapeutic products, manufacture of the pharmacological agents, etc. All this poses major challenges before gene therapies can be approved by national or international drug agencies [1].
Although the applications of “gene editing” using CRISPR-Cas9 technology have gained attention in recent years, traditional “gene therapy” continues to be used. Rather than editing genes, it introduces DNA from a gene or genetic information into the recipient genome for therapeutic purposes (the topic of CRISPR gene editing was discussed at the “Congress on Genetic Research: Possibilities and Risks. An approach from Bioethics”, organized by the Catholic University of Valencia in July 2024).
Below, we present an example of the application of traditional gene therapy to correct a congenital disease.
DB-OTO gene therapy for the treatment of congenital deafness in children
Permanent congenital hearing loss affects about 2 out of every 1000 children born in the U.S. and, by extension, worldwide. This “rare disease” may be due to a number of causes, the most common of which is a mutation in the OLOF gene, which encodes the protein otoferlin in the hair cells of the human inner ear. An autosomal recessive mutation of this gene—located on the short arm of chromosome 2—causes a form of non-syndromic congenital deafness in more than half of cases. The deafness is due to the non-functionality of otoferlin, which is necessary for communication between the sensory hair cells of the inner ear and the auditory nerve [2]. The traditional surgical treatment in these cases is the cochlear implant, an electronic device that is implanted in cases of profound hearing loss. It replaces the damaged parts of the inner ear, and while it does fully resolve the hearing impairment, it provides partial correction of deafness.
Since congenital deafness is permanent, its treatment became an achievable goal through gene therapy, with the youngest children and those who have not had cochlear implants the most likely to benefit, without the need for lifelong prosthetic devices. Cochlear implants may lead to overall improved spoken language skills among children with profound hearing loss.
However, restoring the function of the OLOF gene would provide natural hearing.
To that end, the biotechnology company Regeneron Pharmaceuticals sponsored the launch of the CHORD clinical trial (NCT05788536) [3]. This is a phase 1/2 trial that commenced in 2022, with completion expected in 2031, involving research centers in the US (9 sites), England (2), Germany (1) and Spain (2) (Hospital Ramón y Cajal in Madrid and Clínica Universidad de Navarra in Pamplona). The main objective of the CHORD project is to develop a “gene therapy” method called DB-OTO to treat children with congenital hearing loss secondary to mutations of the OTOF gene, which encodes otoferlin. The specific objectives of the clinical trial are to learn about the safety of the DB-OTO treatment, determine how well it is tolerated (does not cause ongoing discomfort), and evaluate its efficacy. CHORD is being carried out in two phases. In the initial ascending dose cohort, participants receive a single intracochlear injection of DB-OTO into one ear; in the expansion cohort, participants receive DB-OTO in both ears at the dose selected in Part A. The preliminary results of this trial have been excellent and have recently been published in The New England Journal of Medicine [4].
The preliminary results of the trial so far were presented at the recent annual meeting of the American Academy of Otolaryngology and Head and Neck Surgery Foundation (AAO-HNSF). According to the report, the trial was conducted on a sample of 12 pediatric participants (aged 10 months to 16 years) with profound hearing loss due to mutations in the OTOF gene. The surgical procedure to deliver the DB-OTO gene therapy uses an approach similar to that of cochlear implantation, allowing its use in young infants. All participants had profound hearing loss (as assessed by behavioral pure tone audiometry, PTA) and absence of electrophysiological responses (auditory brainstem response, ABR) at maximum sound levels. PTA is a pure tone audiometry method and measures hearing sensitivity through behavioral responses to sound, while ABR measures the electrical responses of the brainstem to sound emitted at different intensity levels.
Participants received a single administration of DB-OTO by intracochlear infusion. Of these, 9 received gene therapy in one ear and 3 received it in both.
At week 24, an assessment was carried out by measuring PTA. All the participants (11 out of 12; 14 out of 15 ears treated) demonstrated improved hearing: 9 participants experienced hearing improvements at a threshold of below 70 decibels at week 24. This threshold corresponds to a clinical standard that normally does not require cochlear implantation and enables natural acoustic hearing. Notably, 6 participants were able to hear soft speech without assistive devices, and 3 were further able to detect whispers (corresponding to normal hearing sensitivity). One participant who did not meet the primary PTA endpoint at week 24 improved later, achieving nearly normal hearing sensitivity after 48 weeks of treatment. Nine participants also demonstrated an ABR (at less than 90 dB), thus achieving the key secondary endpoint of the trial.
Hearing improvements remained stable or continued to improve in 8 participants up to 72 weeks after treatment. The 3 participants who were followed for 48 weeks also showed significant improvements. One of them demonstrated the ability to identify one- and two-syllable words with no visual cues and was able to respond to distant sounds and speech in noisy environments. In summary, this dataset indicates that the responses to the application of DB-OTO gene therapy in the analyzed sample are consistent, rapid, and robust, and that in cases with longer follow-up, they are also stable.
In terms of safety, the treatment was well tolerated and no DB-OTO-related adverse effects were observed. Only two participants experienced problems unrelated to DB-OTO: one was attributed to a surgical complication of the cochlear implant and the other to a recent vaccination. Some participants experienced transient post-surgical adverse effects, all of which fully resolved.
In light of these results, Regeneron Therapeutics plans to submit the application for approval of the DB-OTO treatment to the US Food and Drug Administration (FDA), with submission to the European Medicines Agency (EMA) expected before the end of the year. At the moment it is considered an orphan drug for the treatment of a rare disease.
Open issues and future perspectives
However, at the present time—and probably after the DB-OTO treatment is approved—the main issue is its high cost. For now, it is considered an “orphan drug”, and, given the difficulties in its marketing, it is consequently expensive.
Today, there are thousands of people with hearing loss caused by the mutations addressed by the DB-OTO therapy, and thousands more have other conditions for which gene therapies, gene editing, stem cell therapies, and other therapies at the cutting-edge of biomedical research are currently being developed. Nevertheless, at the moment, and foreseeably from the approval of the DB-OTO treatment, the major issue is the high cost of these types of therapies.
Prices for gene therapies, or those for gene editing already approved by the FDA or the EMA, range from hundreds of thousands to several million Euros. For example, Novartis’s ‘Zolgensma’, a gene therapy drug used to treat spinal muscular atrophy (SMA) in children under 2 years of age, costs 1.5 million Euros per dose (usually one per year); ‘Vertex Pharmaceuticals’ ‘Casgevy™’ treatment for β-thalassemia and sickle cell anemia costs 2.5 million Euros; and Behring GmbH’s ’Hemgenix’ for hemophilia, 3.1 million Euros, etc. Moreover, treatments for these diseases require repeated dosing at variable time intervals.
At the moment, the interest of biotechnology companies—which have to meet the high costs in the research and development of their products—does not point to a downward trend in prices in the short term. The high costs of gene therapy research raise significant methodological, marketing, and policy issues with regard to the assessment of treatments.
A rigorous and thorough evaluation of clinical efficacy is needed to assess the cost of any therapy. All factors must be taken into account, such as the severity of the disease, the likelihood of success of the application, and the number of treatment applications. From a scientific point of view, the value assessment should be based on both costs and health benefits throughout a patient’s life.
A crucial question that needs to be addressed is: what value does a function like hearing (or any given biological function) hold for those dealing with its loss in a child? Is it worth the huge cost to allow a child who is deaf from birth to hear? While in principle we would like to say yes, the issue with the cost is not the value that parents may place on their children’s normal hearing; they would undoubtedly give anything to restore it. The real issue lies in how most people could afford it. This problem is particularly difficult to address in countries like the US, which has a healthcare system based on private insurance, while in countries like Spain, which have a public healthcare system, it raises the question of whether state budgets can cover all cases that could be treated with advanced therapies costing hundreds of thousands or millions of Euros per patient. We can begin to answer this question by looking at the difficulties in the care received by patients with conditions that are even less costly, although in many cases more serious, such as amyotrophic lateral sclerosis (ALS), SMA, or rare diseases in general.
If we consider only diseases treated by gene therapy, the advantage is that it not only corrects or alleviates the symptoms, but eradicates the underlying cause of the disease, or at least extends the intervals between treatments.
In any case, for now, pending improvements in gene therapy techniques that make their application cheaper, the costs are not affordable for all those who wish to undergo treatment. Therefore, the issue is how to reconcile these treatments with the bioethical principle of “justice”, i.e., so that they are equally accessible to all patients.
Nicolás Jouve
Professor Emeritus of Genetics at the University of Alcalá
Member of the Bioethics Observatory of the Catholic University of Valencia
References:
[1] Kohn, D.B., Chen, Y.Y. Spencer, M.J. “Successes and challenges in clinical gene therapy”. Gene Ther 30 (2023) 738–746.
[2] Yasunaga, S., Grati, M., … Petit, C. “A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness”. Nature Genet. 21 (1999) 363-369.
[3] NCT05788536 A Study of DB-OTO, an Adeno-Associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations (CHORD)
[4] Valayannopoulos V, Bance M, Carvalho DS, … Whitton JP; CHORD Study Group. “DB-OTO Gene Therapy for Inherited Deafness”. N Engl J Med. 2025 Oct 12.
