Disease Mechanisms and Repair of Neural and Skeletal Tissue

Current work focuses on modelling human rare diseases and engineering skeletal tissue using patient-derived stem cells to address basic biological questions and harness the acquired knowledge to develop novel therapeutic approaches.    

Rare Disease Research

Acrodysostosis (ACRDYS)

Acrodysostosis (ACRDYS) is a group of autosomal dominant chondrodysplasias presenting extensive facial dysmorphism, brachydactyly, frequent developmental delay and, depending on the gene mutation, intellectual disabilities (predominantly in ACRDYS2) or hormone resistance (predominantly in ACRDYS1). Mutations in PRKAR1A (type 1A regulatory subunit of protein-kinase-A, PKA) and PDE4D (cAMP-specific phosphodiesterase-4D) genes cause ACRDYS1 and ACRDYS2, respectively. Both ACRDYS forms show reduction in activity of the cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling pathway. Nonetheless, there are differences in disease presentation. Current treatments are not specific, have severe side-effects and do not prevent the manifestations from worsening over time.

Key aims include:

• Understand how mutated PRKAR1A and PDE4D lead to the different ACRDYS phenotypes, with a focus on neural and skeletal tissue, although they are both components of the cAMP/PKA signalling pathway, in order to identify key druggable targets depending on which gene is affected for disease-specific and tissue-specific therapy development.
• Investigate underlying molecular mechanisms and pharmacological regulation of PDE4D activity to accelerate our understanding of intellectual disabilities in ACRDYS2, and compare potential therapeutic interventions using relevant readouts of efficacy using human disease models we have generated.

Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. DMD is an X-linked recessive birth defects resulting in progressive and fatal muscle wasting and weakness. Cognitive impairment is also observed DMD patients, consistent with expression of several dystrophin isoforms in the human brain, where they are developmentally regulated. The basis of dystrophin-associated neural pathologies in DMD patients has yet to be fully elucidated hence we are using human neural cells differentiated from induced pluripotent stem cells (iPSCs) carrying DMD mutations to model the disease.

Key aims include:

• Further elucidate the role of astrocytes in neuronal patology and assess a possible involvement in blood brain barrier defects.
• Assess the behaviour of dystrophic neurones and glial cells lacking different dystrophin isoforms to elucidate mechanisms underlying neural deficits in Duchenne brains and pathways that could be targeted for therapeutic purposes.

Cartilage Bioengineering Research

Congenital head and neck defects that can result in dramatically impaired structure and function occur in 1/1000 live births (http://www.eurocat-network.eu). Significantly, over 800 new-borns a year present with major ear abnormalities, predominantly microtia (underdeveloped external ear) or anotia (absent external ear), but also mid-face defects. In addition, damage to cartilages can be caused by trauma or tumour resection.

Key aims include:

• Bioengineering mature stable cartilage tissue suitable for reconstructive surgery using autologous stem cells from tissues that can be harvested using minimally invasive procedures hence avoiding donor site morbidity (e.g. adipose tissue-derived stem cells, cartilage progenitor cells from remnants of microtic ears).
• Assess potential for allogeneic use of umbilical cord-derived stem cells, induced pluripotent stem cells and paediatric adipocyte-derived stem cell for cartilage. bioengineering.