scholarly journals AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure

2021 ◽  
Author(s):  
Kai Xia ◽  
Fulin Wang ◽  
Xingqiang Lai ◽  
Peng Luo ◽  
Hong Chen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Deficient Mouse ◽  
Proof Of Concept ◽  
Adeno Associated Virus ◽  
Promising Therapeutic Approach ◽  
Efficient Vector

Abstract Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we used a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of genetic LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screened several adeno-associated virus (AAV) serotypes and identified AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observed considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr−/− mice. This gene therapy substantially recovered sexual development, partially restored spermatogenesis and effectively produced fertile offspring. Furthermore, these favorable effects could be reproduced in adult Lhcgr−/− mice. Our proof-of-concept experiments in this mouse model demonstrate that AAV-mediated gene therapy may represent a promising therapeutic approach for patients with genetic LCF.

scholarly journals AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure

2021 ◽  
Author(s):  
Kai Xia ◽  
Fulin Wang ◽  
Xingqiang Lai ◽  
Peng Luo ◽  
Hong Chen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Deficient Mouse ◽  
Proof Of Concept ◽  
Adeno Associated Virus ◽  
Promising Therapeutic Approach ◽  
Efficient Vector

Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we used a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of genetic LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screened several adeno-associated virus (AAV) serotypes and identified AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observed considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr-/- mice. This gene therapy substantially recovered sexual development, partially restored spermatogenesis and effectively produced fertile offspring. Furthermore, these favorable effects could be reproduced in adult Lhcgr-/- mice. Our proof-of-concept experiments in this mouse model demonstrate that AAV-mediated gene therapy may represent a promising therapeutic approach for patients with genetic LCF.

scholarly journals A factor IX-deficient mouse model for hemophilia B gene therapy

1997 ◽  
Vol 94 (21) ◽  
pp. 11563-11566 ◽  
Author(s):  
L. Wang ◽  
M. Zoppe ◽  
T. M. Hackeng ◽  
J. H. Griffin ◽  
K.-F. Lee ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Factor Ix ◽  
Hemophilia B ◽  
Deficient Mouse

scholarly journals Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

2019 ◽  
Vol 116 (10) ◽  
pp. 4496-4501 ◽  
Author(s):  
Omar Akil ◽  
Frank Dyka ◽  
Charlotte Calvet ◽  
Alice Emptoz ◽  
Ghizlene Lahlou ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
Therapeutic Option ◽  
The Other ◽  
Therapeutic Window ◽  
Congenital Deafness ◽  
Adeno Associated Virus ◽  
Coding Sequence ◽  
Packaging Capacity

Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5′ and the other the 3′ portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea ofOtof−/−mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5′ and 3′ cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.

Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood

2021 ◽  
Vol 32 (7-8) ◽  
pp. 405-419
Author(s):  
Arsen S. Hunanyan ◽  
Boris Kantor ◽  
Ram S. Puranam ◽  
Courtney Elliott ◽  
Angela McCall ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Adeno Associated Virus ◽  
Alternating Hemiplegia Of Childhood

Leydig cell resistance to the cytotoxic effect of ethylene dimethanesulphonate in the adult rat testis

1985 ◽  
Vol 105 (3) ◽  
pp. 311-NP ◽  
Author(s):  
I. D. Morris
Keyword(s):  
Seminal Vesicle ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Male Rats ◽  
Cell Physiology ◽  
Testis Weight ◽  
Endocrine Activity ◽  
Adult Rat ◽  
Seminal Vesicle Weight

ABSTRACT Weekly doses of the Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) were administered to adult male rats in an attempt to study the endocrine activity of the testis in the absence of Leydig cells. One week after the first dose serum testosterone and LH concentrations and seminal vesicle weights were close to levels in castrated rats and testicular human chorionic gonadotrophin (hCG) binding was severely depressed. These changes were maintained for a further week but subsequently began to return to, but did not achieve, control levels. After six weekly doses seminal vesicle weight and serum testosterone concentrations were significantly higher than in the castrated rats. Serum LH concentrations were declining towards control values at 4 weeks but had risen again at 6 weeks. Serum FSH concentrations were raised to about 50% of the value in castrated rats throughout the period studied. Testis weight and hCG binding, which initially fell, were partially restored at 6 weeks and spermatogenesis was recovering. The data show that responses of the testis to multiple doses of EDS are similar to those after a single dose. This apparent resistance indicates that the regenerating Leydig cells are functionally different from the mature Leydig cell. The similarities between the maturing Leydig cell seen after EDS destruction and those in the immature rat suggest that EDS will provide a valuable model for the investigation of Leydig cell physiology. J. Endocr. (1985) 105, 311–316

Effects of recombinant human FSH in immature hypophysectomized male rats: evidence for Leydig cell-mediated action on spermatogenesis

1994 ◽  
Vol 141 (3) ◽  
pp. 449-457 ◽  
Author(s):  
T Matikainen ◽  
J Toppari ◽  
K K Vihko ◽  
I Huhtaniemi
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Serum Testosterone ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Spermatogenic Cells ◽  
Hypophysectomized Rats ◽  
First Time ◽  
Recombinant Human Fsh

Abstract The mode of FSH actions within the testis was studied in immature hypophysectomized male rats by treatment with recombinant human FSH (recFSH, Org 32489). To elucidate the involvement of Leydig cells and androgens in the maintenance of spermatogenesis in FSH-treated hypophysectomized rats further, the recFSH treatment was given both alone and after destruction of Leydig cells with ethane-1,2-dimethane sulphonate (EDS). Three days after hypophysectomy (at 31 days of age) the rats were given one i.p. injection of vehicle or EDS and, 4 days later, they were implanted with osmotic minipumps releasing either 0·9% (w/v) NaCl or 1 IU recFSH/day. Recombinant FSH alone increased testicular weights 2·5-fold in 7 days (P<0·01). The effect of FSH was similar in EDS-pretreated rats (P<0·01). Testicular testosterone increased from 6·5 ± 1·6 to 16·9 ± 5·3 (s.e.m.) pmol/g tissue (P<0·05) and serum testosterone from 0·12 ± 0·02 to 0·22 ± 0·03 nmol/l (P<0·05) when the rats were treated with recFSH. EDS alone did not affect testicular testosterone but, when combined with recFSH, it totally abolished the stimulatory effect of FSH on testosterone. Testicular binding of 125I-labelled iodo human chorionic gonadotrophin (hCG) and 125I-labelled iodo recFSH was increased 2·5- and 2·1-fold respectively with recFSH treatment (P<0·01). EDS, either alone or with FSH, abolished specific testicular hCG binding (P<0·01), but had no effect on that of recFSH. However, FSH increased its own receptors only in animals not treated with EDS. Histological analysis of the testes revealed that the diameters of the seminiferous tubules increased from 115 ± 6·1 to 160 ± 7·2 μm (P<0·05) with recFSH, and a comparable increase was observed when EDS treatment preceded that of recFSH (143 ± 1·5 μm, P<0·05 vs. controls). Quantification of the spermatogenic cells indicated that recFSH supported the progression of spermatogenesis, as shown by increased number of meiotic and haploid spermatogenic cells (P<0·05). In all EDS-treated animals, spermatogenesis was severely disturbed and only a few spermatids were seen. In conclusion: (1) these results further support the suggestion that FSH has indirect stimulatory effects on Leydig cell function, (2) the completion of meiosis and spermiogenesis are supported by FSH, the effect of which is enhanced by the presence of Leydig cells, suggesting its dependence on androgens, and (3) we show for the first time that FSH is able to stimulate its own receptors only in the presence of Leydig cell-derived factors, probably androgens. Journal of Endocrinology (1994) 141, 449–457

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