SLMS Academic Careers Office

Grand Challenges

29. Human amniotic fluid-derived induced pluripotent stem cells for the treatment of osteogenesis imperfecta.

Supervisor Pair: Pascale V Guillot and Timothy R Arnett Potential Student’s Home Department: Institute for Women's Health

Babies with brittle bone disease, or osteogenesis imperfecta (OI), are born with fragile bones that break easily.  For most babies with OI, everyday activities can lead to fractures at any time, often from little or no apparent cause.  All affected babies experience other problems, including muscle weakness, hearing loss, curved bones, scoliosis, brittle teeth, skeletal deformities, and respiratory problems.  OI starts to manifest before birth in utero, lasting throughout a person’s lifetime.  It is diagnosed commonly at the mid-pregnancy, high-resolution fetal ultrasound scan, where the characteristic short long bones and fractures are already present and detectable. Around one baby in every 10,000 is affected in the UK.

There is at present no cure for OI.  The only pharmaceutical treatments are palliative, failing to address the underlying bone brittleness.

OI is caused by genetic mutations that affect the production of collagen type I, the main component of the bones.  Bone is a composite formed of the organic matrix (dense collagen type I fibres produced by osteoblasts) that provides tensile strength and hard minerals (mainly hydroxyapatite) that are added to the matrix to provide compressive strength.  Because of this structure, the bones can bend and recover their shape, and carry the weight of an individual without breaking. In OI patients, the collagen is abnormal and mineralization is disorganized.  As a consequence, the bones become brittle and break sharply without plastic deformation.

We have used an experimental model of OI (oim mice), which suffer from fragile bones and multiple fractures identified at birth.  We have been able to decrease fracture rate by two-third by transplanting oim mice in utero with human mesenchymal stem cells (MSCs).  As a result, oim bones were stronger and break less easily.  We also showed the donor cells became bone cells in oim mice and participated to bone formation. Because we need considerably more cells to treat humans than mice, we need to expand the cells in vitro before transplantation to treat human babies.  Unfortunately, these cells cannot be expanded to large numbers without losing their capacity to regenerate bones. 

In this project, you will first reprogram human cells to pluripotency (induced pluripotent stem cells, iPS cells).  As a result, these rejuvenated cells will regain the capacity to be expanded to large numbers without aging and without losing their regenerative characteristics.  You will then transplant these cells in oim fetuses to evaluate their bone repair and regeneration potential (prenatal cell therapy) and determine optimal timing of injection (prenatal vs. perinatal vs. late postnatal).  Finally, using optimal timing of transplantation as determined above, you will assess whether a second transplantation is required to maintain the long-term therapeutic benefits of the first iPSC-MSCs injection.  This pre-clinical project will pave the way for human trials for OI using translatable iPSC technology.  We anticipate 3 publications to high impact factor peer-reviewed journals.  The project will be co-supervised by Professor Tim Arnett, who is a leading expert on osteoblast and osteoclast function, and by Dr Pascale V Guillot, whose group was the first to reprogram human cells to pluripotency using chemicals only, without ectopic expression of transcription factors.  Together they run projects to develop iPS cell-based therapy to treat bone pathologies.