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Link to original content: http://pubmed.ncbi.nlm.nih.gov/32173115/
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Review
. 2020 Sep 1:394:107931.
doi: 10.1016/j.heares.2020.107931. Epub 2020 Mar 5.

Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction

Michelle L Hastings  1 , John V Brigande  2
Affiliations
Review

Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction

Michelle L Hastings et al. Hear Res. .

Abstract

Disabling hearing loss is expected to affect over 900 million people worldwide by 2050. The World Health Organization estimates that the annual economic impact of hearing loss globally is US$ 750 billion. The inability to hear may complicate effective interpersonal communication and negatively impact personal and professional relationships. Recent advances in the genetic diagnosis of inner ear disease have keenly focused attention on strategies to restore hearing and balance in individuals with defined gene mutations. Mouse models of human hearing loss serve as the primary approach to test gene therapies and pharmacotherapies. The goal of this review is to articulate the rationale for fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. The differential onset of hearing in mice and humans suggests that a prenatal window of therapeutic efficacy in humans may be optimal to restore sensory function. Mouse studies demonstrating the utility of early fetal intervention in the inner ear show promise. We focus on the modulation of gene expression through two strategies that have successfully treated deafness in animal models and have had clinical success for other conditions in humans: gene replacement and antisense oligonucleotide-mediated modulation of gene expression. The recent establishment of effective therapies targeting the juvenile and adult mouse provide informative counterexamples where intervention in the maturing and fully functional mouse inner ear may be effective. Distillation of the current literature leads to the conclusion that novel therapeutic strategies to treat genetic deafness and imbalance will soon translate to clinical trials.

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Figures

Figure 1:
Figure 1:. Temporal framework for therapeutic intervention in the mouse and human inner ears.
A, The mouse inner ear at E11.5 is a fluid-filled vesicle lined by otic epithelial progenitor cells that contribute to the sensory and nonsensory structures of the inner ear. A subpopulation of otic progenitors gains neural competence and migrates out of the vesicle to establish the nascent cochleovestibular ganglion (green) that will innervate auditory and vestibular hair cells. Hearing in the mouse can be detected by acoustic startle responses at ~P12. Therapeutic strategies aimed at the restoration of hearing and balance in mouse models of human hearing loss are most effective when performed from P0-P5 after which effectiveness rapidly declines or is eliminated entirely. P0-P5 is represented as the Postnatal Window of Efficacy. B, The human inner ear at 8 weeks gestational age (GA8) is morphologically similar to the E11.5 mouse otic vesicle. Hearing in humans may be detected by acoustic startle responses as early at GA19 during the second trimester of pregnancy. The postnatal window of efficacy in the mouse closes one week prior to hearing onset at P12. A proposed Prenatal Window of Efficacy in the human fetus may close as early as GA18, one week prior to hearing onset at GA19. Abbreviations: AC, anterior crista; ASC, anterior semicircular canal; CVB, cochleovestibular ganglion; ES, endolymphatic sac; LC, lateral cristae; LSC, lateral semicircular canal; PC, posterior crista; PSC, posterior semicircular canal; SM, saccular macula; UM, utricular macula. Inner ear schematics are not drawn to scale.
Figure 2:
Figure 2:. Bioactive reagent delivery into the mouse otic vesicle and amniotic cavity.
A, Schematic representation of transuterine microinjection into the otocyst at E12.5. The microinjection pipette is advanced through the uterus (red line), the visceral yolk sac (black line), and amnion (green line) and inserted the right otic vesicle. B, The E12.5 otocyst is filled with fast green tracer dye delivered with a pressure injection system. The tapered endolymphatic duct (ED) presents dorsally and the clam shell shape of the vestibule ventrally are morphological correlates of successful otic vesicle targeting. C, Schematic representation of transuterine microinjection into the amniotic cavity at E13.5. D, The amnion is pierced where it tents between the snout and right hind limb (RH). The fast green injectate (I) is visible as a plume beneath the snout in the lateral view during the injection. One minute after completing the injection, injectate has diffused throughout the amniotic cavity obscuring the face and abdomen of the embryo. The injection in B was performed with the uterus resected and that in D was performed in vitro with the embryo and extraembryonic membranes intact to facilitate imaging. Abbreviations: ac, amniotic cavity; ec, exocoelomic cavity; M, midbrain; P, embryonic component of the placenta; T, tail; ysc, yolk sac cavity.
Figure 3:
Figure 3:. Major types of oligonucleotide strategies being investigated and developed as therapeutics.
The major types of oligonucleotides that are being pursued for the treatment of human conditions are shown. A. Antisense oligonucleotides (ASOs). ASOs can be subdivided into two major types. The first type is RNase H-dependent gapmers that have core DNA nucleotides that, upon base-pairing to complementary RNA render the RNA susceptible to cleavage by RNase H, an endoribonuclease the cleaves the phosphodiester bonds of RNA that is hybridized to DNA. In contrast, the second major type of ASO is the steric block ASOs that are designed to create a steric block to processing of mRNA by limiting access to RNA processing proteins and protein complexes or disrupting RNA secondary structure or RNA/RNA interactions, for example. Steric block ASOs are chemically modified RNA-like molecules that, when bound to target RNA, do not elicit degradation but instead, depending on where they hybridize, can modify mRNA transcription, splicing, polyadenylation, stability and translation, for example. Steric blocking ASOs can also hybridize to non-coding RNAs such as miRNAs (anti-miRs, antagomirs, AMO) to block miRNA activity. B. RNA interference. Oligonucleotides that induce RNA interference are designed to down-regulate target gene expression by recruiting the cellular RNA-induced silencing complex (RISC). Two general strategies include siRNAs that are completely complementary to a single target and specifically repress a single target and miRNAs (miRNA mimics) that have only partial complementary to target RNAs and thereby can suppress numerous targets. Delivery of RNAi-inducing nucleic acids to cells can involve delivery of siRNA directly or can be achieved by delivery of a viral-vector expressing a longer RNA sequence that forms a short-hairpin RNA (shRNA) that is a substrate for cleavage to create an siRNA molecule substrate for the RISC complex. C. Other types of oligonucleotide strategies. Aptamers are short oligonucleotides designed to form secondary structures that are recognized by proteins and modulate its activity by binding and inhibiting receptor binding or enzymatic activities. Oligonucleotides can also act as decoys and binding sites for proteins to sequester them and thereby limit activity by mimicking binding sites. Others, such as CpG oligonucleotides, are intended for stimulation of the immune system upon recruitment of protein such as TLR9. Catalytic nucleic acids such as DNAzymes and ribozymes are oligonucleotides that bind to target and perform a chemical reaction. These activities can be used to cleave or edit their targets and also have value as diagnostics and in biosensing.
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