ESPEYB20 4. Differences of Sexual Development (DSD) and Gender Incongruence (GI) Sexuality, Fertility and Fertility Optimization in DSD (3 abstracts)
4.3. AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure
Xia K , Wang F , Lai X , Dong L , Luo P , Zhang S , Yang C , Chen H , Ma Y , Huang W , Ou W , Li Y , Feng X , Yang B , Liu C , Lei Z , Tu X , Ke Q , Mao FF , Deng C & Xiang AP
Cell Rep Med. 2022 Nov 15;3(11):100792. doi: 10.1016/j.xcrm.2022.100792. Epub 2022 Oct 20. PMID: 36270285; PMCID: PMC9729833
Brief summary: In this in vivo study, Xia et al. demonstrate that AAV-mediated gene therapy recovers testosterone levels, restarts sexual development, restores spermatogenesis, and produces fertile offspring in a mouse model of Leydig cell failure (LCF).
A null mutation in the gene encoding luteinizing hormone/choriogonadotrophin receptor (Lhcgr) causes a hereditary LCF in mice which is characterized by a reduction in testosterone levels, stunted sexual development, defective spermatogenesis, and infertility. Mice, homozygous for the mutation in Lhcgr (Lhcgr-/-) mimic the phenotype of LCF in humans.
In this study, Xia K et al. used recombinant adeno-associated virus (AAV) gene delivery vectors for in vivo gene therapy. AAV8 was identified as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection in the testis of Lhcgr-/- pubertal mice.
AAV8-mediated gene therapy in pubertal Lhcgr-/-mice partially increased serum testosterone levels and substantially improved sexual development. Testosterone restoration of approximately 30% in AAV8-Lhcgr-injected Lhcgr-/- mice recovered full spermatogenesis, and effectively gave rise to offspring. Furthermore, these AAV8-Lhcgr gene therapy-derived mice were able to produce a second generation by natural mating.
AAV8 showed a clear tropism to target progenitor Leydig cells and showed an absence of vector infection in germ cells and Sertoli cells by interstitial injection in the testis of Lhcgr-/- pubertal mice. Furthermore, tail DNA from the offspring born after AAV8-Lhcgr treatment did not contain any vector sequence signals, suggesting that AAV8 did not integrate into the genomes of the offspring which would otherwise result in off-target genomic effects.
Adult mice responded to AAV-mediated gene therapy as effectively as pubertal mice, as demonstrated by similar increments of testosterone production and restart of sexual development. The researchers also showed tropism of the AAV8 vector to progenitor Leydig cells but not germ cells or Sertoli cells in monkey testes.
Overall, the findings of this study suggest that in vivo gene therapy seems a promising future treatment for the group of DSD conditions associated with impaired testosterone biosynthesis and LCF such as 3ß-hydroxysteroid dehydrogenase type 2 (3ß-HSD2) deficiency, cytochrome P450 oxidoreductase (POR) deficiency, CYP17A1 deficiency, or 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) deficiency. One open question remains about the short effect o such treatment which would be due to the loss of the vector genome during progenitor Leydig cell proliferation because of the nonintegrating nature of AAV vectors.
Volume 20
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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