First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model

Kian Chuan Sia,Siti Humairah Mohd Rodhi,Kok Onn Lee,Shu Uin Gan,Zhen Ying Fu,John J Kopchick,Michael J Waters

doi:10.1038/s41434-022-00313-w

Kian Chuan Sia, Siti Humairah Mohd Rodhi + Show 5 more

Open Access

https://doi.org/10.1038/s41434-022-00313-w

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Abstract

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4–5-week-old Laron dwarf mice (GHR−/−) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

Highlights

Laron first described the syndrome of short stature with growth hormone (GH) insensitivity, and elevated GH with undetectable insulin-like-growth factor 1 (IGF1) in 1966 [1,2,3]
We further explored the potential of AAV8 vector to express mouse GHR (mGHR) regulated by the same liver-specific hybrid liver-specific promoter (HLP) promoter for treatment of Laron dwarf mice
We have successfully demonstrated for the first time that the associated virus (AAV) vector can be used to treat Laron dwarfism with a single AAV injection dose using a mouse model with disruption of the mGHR gene [18]

Summary

Introduction

Laron first described the syndrome of short stature with growth hormone (GH) insensitivity, and elevated GH with undetectable insulin-like-growth factor 1 (IGF1) in 1966 [1,2,3]. We have attempted to use a strategy of increasing IGF1 in an animal model by replacing the disabled GH-receptor (GHR) gene using a viral vector with a liver-specific transcriptional regulatory sequence, since this organ is the major source of circulating IGF1. This approach should increase circulating IGF1 without any change in GHR in tissues other than the liver. There is persistent gene expression for more than 10 years following a single dose of vector administration, making AAV gene therapy an attractive treatment with potentially significant therapeutic outcomes [17]

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