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Review
. 2024 Jan 24:18:1272786.
doi: 10.3389/fnins.2024.1272786. eCollection 2024.

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss

Linke Li #  1 , Tian Shen #  1 , Shixi Liu  1 , Jieyu Qi  2 , Yu Zhao  1
Affiliations
Review

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss

Linke Li et al. Front Neurosci. .

Abstract

Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from a multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis of auditory development and the growing compendium of deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered a relatively secure vector for gene therapy in clinical trials, can deliver various transgenes based on gene therapy strategies such as gene replacement, gene silencing, gene editing, or gene addition to alleviate diverse types of SNHL. This review delved into the preclinical advances in AAV-based gene therapy for SNHL, spanning hereditary and acquired types. Particular focus is placed on the dual-AAV construction method and its application, the vector delivery route of mouse inner ear models (local, systemic, fetal, and cerebrospinal fluid administration), and the significant considerations in transforming from AAV-based animal model inner ear gene therapy to clinical implementation.

Keywords: adeno-associated virus; delivery route; dual-AAV; gene therapy; sensorineural hearing loss.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of inner ear delivery routes, structure of the organ of corti, and causal genes associated with hearing loss in preclinical studies. (A) The four local delivery routes to the inner ear include (1) RWM injection, (2) RWM injection combined with CF, (3) cochleostomy, (4) utricle injection, and (5) canalostomy. (B) Structure organ of corti. ASCC, anterior semicircular canal; PSCC, posterior semicircular canal; LSCC, lateral semicircular canal; RWM, round window membrane; CF, semicircular canal fenestration.
Figure 2
Figure 2
Overview of dual-AAV system restoring the expression of the large therapeutic proteins. The CDS of a gene is bifurcated into two sections (5’ and 3’), each of which is encapsulated into two AAVs. When co-transduced into the same cell, various methods are be used to reestablish the expression of large therapeutic proteins. This restoration process involves the recombination of the two segments at multiple stages: the DNA level (A), the pre-mRNA level (B), or directly at the protein level (C). (A) Reconstitution full-length CDS: the trans-splicing method involves the reconstitution of the full-length CDS through the process of concatemerization of the two vectors mediated by ITRs, followed by the splicing signals which eliminate the ITR structure. In the overlapping method, both vectors contain an overlap region, which functions as a homologous sequence, enabling the two gene segments to recombine effectively. The hybrid method design of the two vectors imitates that of the trans-splicing method, but with an added HR positioned downstream of the SD in the 5’-vector and upstream of the SA in the 3’-vector. The full gene can be reassembled either through ITR-mediated concatemerization or homologous recombination, followed by splicing to remove the intermediate sequence. (B) Reconstitution of full-length mRNA: in this approach, the two mRNA pair up via their complementary HDs, followed by splicing which results in the elimination intermediate sequence. (C) Reconstitution of full-length protein: the self-recognition and self-excision of inteins facilitate pairing the two half polypeptides to form the full-length protein. 5’CDS, 5’ portion of the coding sequence; 3’CDS; 3’ portion of the coding sequence; AAV, adeno-associated virus; ITR, inverted terminal repeat; HR, highly recombinogenic exogenous sequence; SD, splicing donor; SA, splicing acceptor; HD, hybridization domain; prom, promoter; polyA, polyadenylation (figure modified from Tornabene and Trapani, 2020).
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