Stem cell & gene therapy to treat osteogenesis imperfecta: hype or hope

treat osteogenesis imperfecta

Pascale V Guillot from University College London, Elizabeth Garrett Anderson Institute for Women’s Health, explains stem cell and gene therapy to treat osteogenesis imperfecta, but is this hype or hope?

A genetic syndrome that affects bones

Osteogenesis Imperfecta (OI) is a hereditary disorder occurring in 1:10,000 births and characterised by osteopenia (bone loss) and skeletal fragility (fractures). Secondary features include short stature, skeletal deformities, blue sclera and dentinogenesis imperfect. (1) There is a large clinical variability in OI, and severity ranges from mild to lethal, based on radiological characteristics. Genetically, OI is a collagen-related syndrome. Type I collagen is a heterotrimeric helical structure synthesized by bone-forming cells (osteoblasts), and it constitutes the most abundant protein of the skeletal organic matrix. (2) Synthesis of type I collagen is a complex process. (3) Collagen molecules are cross-linked into fibrils (which confer tensile strength to the bones). Those are then mineralised by hydroxy-apatites (which provides compressive strength) and assembled into fibres.

Dominant mutations in either the COL1A1 or the COLA1A2 genes are responsible for up to 90% of all OI cases. These mutations (more than 1,000 of which have been identified) lead to impairment of collagen structure and production, which in either quantitative or qualitative bone extracellular matrix (ECM) defects. Mutations affecting ECM structure have serious health consequences because the skeleton protects visceral organs and the central nervous system and provides structural support. Bones also store fat in the yellow bone marrow found within the medullary cavity, whilst the red marrow located at the end of long bones is the site of haematopoiesis. In addition, the ECM constitutes a reservoir of phosphate, calcium, and growth factors, and is involved in trapping dangerous molecules.

The rationale behind cell therapy

Stem cell therapy for OI aims to improve bone quality by harnessing the ability of mesenchymal stem cells (MSC) to differentiate into osteoblasts, with the rationale that donor cells would engraft into bones, produce normal collagen and function as a cell replacement. Stem cells have, therefore, been proposed for the treatment of OI (4) and, in particular, prenatal foetal stem cell therapy (foetal stem cells injected into a foetus, i.e. foetal-to-foetal) approach, which offers a promising route to effective treatment. (5) Human foetal stem cells are more primitive than stem cells isolated from adult tissues and present advantageous characteristics compared to their adult counterparts, i.e. they possess a higher level of plasticity, differentiate more readily into specific lineages, grow faster, senesce later, express higher levels of adhesion molecules, and are smaller in size. (6,7) Prenatal cell therapy capitalises on the small size of the foetus and its immunological naivete. In addition, stem cells delivered in utero benefit from the expansion of endogenous stem cells and may prevent organ injury before irreversible damage. (8)

However, human foetal stem cells used are isolated from either foetal blood drawn by cardiac puncture, either during termination of pregnancy or during ongoing pregnancy, albeit using an invasive procedure associated with a high risk of morbidity and mortality for both the foetus and the mother (9). Foetal cells can also be isolated from the first-trimester liver (following termination of pregnancy) and such cells are currently used in The Boost Brittle Bones Before Birth (BOOSTB4) clinical trial, which aims to investigate the safety and efficacy of transplanting foetal derived MSCs prenatally and/or in early postnatal life to treat severe Osteogenesis Imperfecta (OI) (10). Alternatively, foetal stem cells can be isolated during ongoing pregnancy from the amniotic fluid, either during mid-trimester amniocentesis or at birth (11,12) or from the chorionic villi of the placenta during first-trimester chorionic villi sampling (13).

We have demonstrated that human fetal stem cells isolated from first trimester blood possess superior osteogenic differentiation potential compared to adult stem cells isolated from bone marrow and to fetal stem cells isolated from first trimester liver. We showed that in utero transplantation of these cells in an experimental model of severe OI resulted in a drastic 75% decrease in fracture rate incidence and skeletal brittleness, and improvement of bone strength and quality.(14) A similar outcome was obtained using placenta-derived foetal stem cells (15) and amniotic fluid stem cells following perinatal transplantation into experimental models. (16,17)

The future for OI

Understanding the mechanisms of action of donor cells will enable the engineering of donor cells with superior efficacy to stimulate bone formation and strengthen the skeleton. Despite their potential to differentiate down the osteogenic lineage, there is little evidence that donor cells contribute to regenerating bones through direct differentiation, due to the very low level of donor cell engraftment reported in all our studies. When placed in an osteogenic microenvironment in vitro, foetal stem cells readily differentiate into osteoblasts and produce wild type collagen molecules. However, there are insufficient proofs that collagen molecules of donor cell origin contribute to the formation of the host bone ECM to confer superior resistance to fracture.

It is now well accepted that stem cells can influence the behaviour of target cells through the release of paracrine factors and, therefore, contribute to tissue regeneration indirectly. We have indeed recently shown that donor stem cells stimulate the differentiation of resident osteoblasts, which were unable to fully mature in the absence of stem cell treatment. (16,17) We are now focusing our efforts on understanding the precise molecular mechanisms by which donor cells improve skeletal health to counteract bone fragility caused by various OI-causative mutations.


  1. Am J Med Genet A 164A, 1470–1481 (2014).
  2. Annu Rev Biochem 78, 929–958 (2009).
  3. Nat Rev Dis Primers 3, 17052 (2017).
  4. J R Soc Interface 7 Suppl 6, S689–706 (2010).
  5. Stem Cells Transl Med 3, 255–264 (2014).
  6. Semin Reprod Med 24, 340–347 (2006).
  7. Stem Cells 25, 646–654 (2007).
  8. Mol Ther Methods Clin Dev 5, 16020 (2016).
  9. Hum Reprod 23, 2427–2437 (2008).
  10. Eur J Hum Genet 27, 1244–1253 (2019).
  11. Nat Biotechnol 25, 100–106 (2007).
  12. Curr Stem Cell Res Ther 8, 73–81 (2013).
  13. PLoS One 7, e43395 (2012).
  14. Blood 111, 1717–1725 (2008).
  15. Stem Cells Dev 23, 262–276 (2014).
  16. Sci Rep 6, 39656 (2016).
  17. Sci Data 5, 180100 (2018).


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  1. Thank you for the information ..I need to know when can be gene therapy is successful for 2 year old daughter she is suffering from mild oi type 1 .please I beg you people make it fast as soon as possible ..I can’t see her suffering in deformetis bone I pary for God to you people to be succes in this …with heartly


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