Unravelling the role of NBAS in skeletal development: towards treatment for NBAS-related human phenotype

Brittle Bone Disease, also referred to as Osteogenesis Imperfecta (OI) affects 1 in 20,000 live births and results in a childhood with frequent fractures, reduced mobility and joint problems. Bones and joints are predominantly composed of type 1 collagen which provides a strong framework for these tissues. OI is usually caused due to a problem with type 1 collagen production and/or processing. This condition can have a huge impact on patients and their families due to child protection proceedings, recurrent hospital admissions with fractures and surgical procedures.
Sheffield has the largest patient group in the Paediatric population for OI and is an internationally renowned centre of excellence treating children with this condition. As lead Geneticist for this service, I provide Genetics input to patients nationally and ensure these patients are given an accurate diagnosis and information regarding their condition, recurrence risks for future pregnancies and risk for extended family members.
As part of my clinical work, I have a group of children with OI in whom the underlying genetic cause has not yet been identified. Advances in genetic technology have allowed us to undertake in-depth genetic studies in these children which have identified changes in a new gene, NBAS. I aim to investigate this form of syndromal OI, where it is not immediately obvious why these gene changes cause bone fragility.
NBAS gene faults results in severe bone fragility but also severe liver failure and immune deficiency. There are no treatments available to cure the condition and given the lack of long term studies to inform families, this condition results in a 'diagnostic odyssey' for patients and their families. Information so far available suggests severe impact on patients with need for costly supportive treatments (Pamidronate and Immunoglobulin replacement therapy) and liver transplant. Therefore, it is important to study this condition and improve quality of life for these patients
I plan to determine why mutations in this particular gene, NBAS, causes bone fragility resulting in severe clinical disability. I have so far been investigating how the cells transports collagen within the cell when NBAS gene is removed from these cells, a pathway that I believe is abnormal in this form of OI. The results are being correlated by data obtained from studying cells obtained from patients. To aid in this endeavour, I plan to develop an animal model (fish) which replicates the clinical presentation seen in humans. Developing an animal model will allow me to test targets that are developed during this proposal in a living organism. My hope is that by understanding what goes wrong in this form of syndromal OI, new treatments may be developed to arrest, or even reverse, the damage seen in this condition.
A primary outcome would be to understand how NBAS affect skeletal development in a fish model and what happens to the liver and immune system in such an animal model. Given NBAS gene changes not only causes bone fragility but also children suffer from several episodes of liver failure (which can be fatal) and immune problems needing recurrent hospital admissions, it is important to research this and develop treatments to make it better.
Although, developing drugs to treat the condition will take several years of work, this proposal aimed at understanding the function of this gene, screening small molecules in fish will be a crucial first step in this process.
A secondary outcome from this proposal would be better insights into collagen transport which would be of clear benefit in OI and bone fragility in the elderly which has a huge disease burden.
This proposal and training elements within it will provide the opportunity to build a strong network of collaborators and key contacts that will help further my career aspirations and propel me in my transition to becoming an independent researcher undertaking world-class research in bone genetics.

During studies to identify genes associated with rare osteogenesis imperfecta (OI) phenotypes, I discovered that the same mutations in NBAS (Neuroblastoma Amplified Sequence) known to be associated with acute liver failure in infants were responsible for skeletal abnormalities in patients with OI. This work was published as a novel cause of bone fragility.
This discovery provides me the opportunity to use tractable animal (zebrafish) research to advance understanding of the mechanisms by which NBAS exerts its effects, develop a fish model that accurately mimics human disease and identify potential new treatments. This would be beneficial to patients with both bone and liver manifestations of disease and could inform on a wider front regarding cell membrane trafficking and effects on collagen processing and secretion.
Patients with NBAS are subjected to a lifetime of recurrent fractures, repeated episodes of acute liver failure needing recurrent hospital admissions and immune deficiency. Developing druggable targets towards making this condition better would have a positive impact on quality of life for patients. I plan to have potential druggable targets elucidated from this study that as part of future Fellowship/ Programme grant will be used to translate into clinical practice.
My long-term career goal is to become a translational clinician scientist focused on patient-oriented research in bone fragility and establish a dynamic, cutting-edge bone genetics research group within University of Sheffield.
In order to progress efficiently towards this goal, my short-term objectives are to obtain further training on practical laboratory skills in bone biology, and animal modelling, which this present application will provide. This is impossible at present with my full time clinical commitments.
This application will provide me a unique combination of practical skills and scientific knowledge to help me achieve independence and prepare for my long-term goal.