Huazhong University of Science and Technology Licenses Prenatal Inner Ear-Targeted Gene Therapy Platform for Fetal Hearing Disorders

Recently, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, released a public notice on the transformation of scientific research achievements, proposing to“A Recombinant Adeno-Associated Virus and Its Application in the Preparation of Gene Therapy Drugs for Inner Ear Targeting During Pregnancy”The relevant patented technologies were transferred to Hangzhou Huier Technical Equipment Co., Ltd. via assignment of patent rights, with the transfer price being1 million yuan。

The core of this technology lies in the use of recombinant adeno-associated virus (AAV) vectors combined with Otogelin and/or Prestin gene promoters, which significantly enhances the gene targeting specificity of AAVs. This advancement not only provides a more effective therapeutic window for gene therapy targeting specific mutations in hereditary deafness but also pioneeringly lays the foundation for clinical fetal gene therapy, holding promise to fill the technical gap in intrauterine inner ear gene therapy during pregnancy.

Gene therapy has made significant progress in the clinical treatment of genetic disorders. The primary cause of hereditary deafness isAbnormal Gene Mutations, As molecular biology research on deafness continues to deepen, the discovery of multiple deafness-related genes has provided precise targets for gene therapy.

In animal experiments, there have been cases where gene therapy has restored hearing in mouse models of hereditary deafness. The intracochlear injection of the relevant vectors is typically performed within 0–2 days after birth in mice. However, mutations in certain genes may cause permanent damage even before birth. For instance, GJB2 and SLC26A4, the two most commonly mutated genes in hereditary deafness, can lead to severe hearing loss at birth when deleted or mutated. Studies have shown that auditory function begins to emerge in mice at 10–14 days after birth, whereas human fetuses exhibit auditory responses at 24–28 weeks of gestation.

However, most existing interventions are implemented after birth. At this stage, the body’s immune system has already matured, making it prone to immune responses following the administration of gene therapy vectors. This reduces vector transduction efficiency and may increase the risk of adverse effects, thereby significantly limiting therapeutic efficacy and safety.

Therefore,Gene Therapy for the Inner Ear During Pregnancy Requires Urgent RefinementOn the one hand, performing viral vector transduction or gene encoding during pregnancy, when the immune system is still immature, facilitates acceptance by early embryonic target cells and enhances the transfection efficiency of gene therapy vectors; on the other hand, early intervention holds promise for achieving superior therapeutic outcomes.

The inner ear consists of the membranous labyrinth and the bony labyrinth. The organ of Corti, formed by highly differentiated specialized regions of the membranous labyrinth, serves as the auditory receptor and is composed of sensory hair cells and supporting cells. Cochlear sensory cells include inner hair cells and outer hair cells, while supporting cells encompass inner pillar cells, outer pillar cells, Deiters’ cells, inner phalangeal cells, inner border cells, and Hensen’s cells.

Traditional viral promoters, such as CMV and CAG, are highly expressed in the embryonic inner ear and lack targeting specificity, which limits the application of viruses during the embryonic stage.

Therefore, it is necessary to combine novel promoters to develop a highly targeted adenovirus for inner ear gene therapy during pregnancy, thereby enhancing the transfection efficiency of relevant vectors and paving the way for new approaches to hearing restoration through gene therapy.

To address clinical challenges such as the early-onset and irreversible nature of pathogenic damage in hereditary deafness, the delayed timing of existing interventions, and the suboptimal targeting of traditional vectors, the research team has developed aA Technical Solution for Expanding the Therapeutic Window and Achieving Precise Targeted Gene Delivery During the Embryonic Stage, with the aim of improving the efficacy and safety of treatment for hereditary deafness.

This patented achievement has achieved multiple breakthroughs in technical design and clinical application, with its core advantages and innovations mainly concentrated inTargeting, Timing of Intervention, and Technical AdaptabilityThese three major dimensions.In terms of targeting precisionInnovatively combining the specific gene promoters of Otogelin and Prestin with adeno-associated virus (AAV) vectors, this approach resolves the technical challenge of generalized expression associated with traditional universal promoters. The Otogelin promoter enables specific expression in non-sensory epithelial cells of the inner ear, allowing precise targeting of supporting cells; meanwhile, the Prestin gene specifically encodes the motor protein of outer hair cells, achieving precise targeting of these cells. Furthermore, expression driven by both promoters occurs prior to the stage of cellular differentiation, providing a molecular basis for targeted embryonic interventions in inner ear diseases caused by defects in different cell types.

In terms of optimizing the timing of intervention,This patent is the first to clearly define the core value of intra-embryonic inner ear injection during pregnancy, advancing the therapeutic window to embryonic days E12.5–E13.5. This approach not only avoids vector-induced immune responses triggered by postnatal immune system maturation but also enables early intervention before pathogenic genes cause permanent damage. Animal studies have confirmed that viral transduction efficiency following embryonic injection is significantly higher than that observed with postnatal day 2 (P2) injection, thereby mechanistically ensuring enhanced therapeutic efficacy.

In terms of technical adaptability,This patent employs the AAV2.7m8 capsid protein, optimized through in vivo directed evolution, to enhance infection efficiency by strengthening its binding affinity to cellular receptors. Furthermore, by incorporating core components such as AAV2 inverted terminal repeats (ITRs) and the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), a recombinant viral vector with stable structure and high expression efficiency was constructed.

In addition, it is also equipped withEstablished a Standardized Technical Protocol for Microinjection into the Embryonic Otic Vesicle, clarifying the compatible carriers and excipient requirements for drug formulations, as well as administration standards, thereby transforming inner ear gene therapy during pregnancy from a theoretical concept into an operable technical system and providing comprehensive technical support for subsequent clinical translation.

The global field of gene therapy for fetal genetic diseases during pregnancy is still in its early exploratory stages, with no mature product pipeline yet established. Related R&D efforts are largely concentrated on a few lethal rare diseases or specific organ-targeted therapies, and disclosed core competitors exhibit differentiated technological approaches and development progress.

AtSmall-Molecule Gene RegulatorsField,Risdiplam, developed by Roche, is a representative product.. As an oral small-molecule gene regulator, the core mechanism of action of this drug isRegulating SMN2 Gene Expression to Increase Levels of Functional SMN Protein. The product was originally approved for the treatment of patients with spinal muscular atrophy (SMA) after birth; subsequent studies have confirmed its favorable placental permeability, allowing it to reach the fetus via oral administration to pregnant women.

In 2025, The New England Journal of Medicine reported a case of compassionate use in which St. Jude Children’s Research Hospital in the United States administered the drug daily to a pregnant woman at 32 weeks’ gestation. Treatment was continued for six weeks and maintained after birth; by the age of two and a half years, the child had not developed any symptoms associated with spinal muscular atrophy (SMA). Analyses of amniotic fluid and umbilical cord blood confirmed the drug’s efficacy, demonstrating that fetal SMN protein levels were significantly higher than those observed in patients who initiated treatment only after birth.

However, this product is currently only at the stage ofCase Stages of “Compassionate Use” During Pregnancy, has not yet entered large-scale clinical trials, is not a direct gene therapy product, requires long-term medication, and lacks organ-specific targeting capability.

AAV Vector Gene Therapyis a key direction in the current research and development of gene therapy during pregnancy, among whichiECURE's ECUR-506Highly promising. This dual-vector gene editing therapy employs a unique delivery system: one vector carries the ARCUS nuclease to cleave the genome at the PCSK9 safe-harbor site, while the other carries a functional OTC gene, enabling precise in vivo gene insertion. It targets ornithine transcarbamylase (OTC) deficiency, a lethal urea cycle disorder that can cause brain damage due to abnormal ammonia metabolism as early as the fetal period. The technological approach holds potential for extension into prenatal treatment during pregnancy.

The research team has currently initiated safety explorations using fetal models. The product is now in Phase I clinical trials for infants, primarily targeting those aged 6.5 months. Plans are in place to subsequently expand its application to fetuses during pregnancy; however, clinical trials related to pregnancy have not yet been launched.

AtVLP Vector Gene EditingField,Technical University of Munich, GermanyR&DENVLPE + Programmable Editor Delivery SystemDemonstrates unique advantages. This system uses virus-like particles (VLPs) as vectors to deliver CRISPR-Cas9, base editors, and other agents in the form of ribonucleoproteins (RNPs) to target cells, with no risk of DNA integration and low immunogenicity.

In mouse models of hereditary retinal diseases (rd6, rd12), this system has achieved precise editing of retinal cells, significantly restoring visual function in the model mice. Given that the retina and inner ear are both sensory organs that undergo early differentiation during embryonic development, and considering the VLP vector’s capability for organ-specific targeting, the research team has initiated preclinical studies using fetal mouse models of hereditary retinal diseases. These studies aim to explore the therapeutic effects of intrauterine injection during pregnancy on congenital retinal disorders such as Leber congenital amaurosis. However, the system has not yet entered human clinical trials, nor has it involved targeted optimization for other organs such as the inner ear.