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Boost Brittle Bones Before Birth

Periodic Reporting for period 1 - BOOSTB4 (Boost Brittle Bones Before Birth)

Reporting period: 2016-01-01 to 2017-06-30

The Boost Brittle Bones Before Birth (BOOSTB4) project is focused on the shared ambition of a group of leading European clinicians, researchers and industrial stakeholders to translate fetal-derived mesenchymal stem cell (MSC) transplantation into the clinic as a therapy for a range of skeletal dysplasias, muscular dystrophies and inborn errors of metabolism with early central nervous system involvement.

What is the problem/issue being addressed?
Osteogenesis Imperfecta (OI) is a debilitating inherited disorder with prenatal onset leading to osteopenia (a medical condition in which the protein and mineral content of bone tissue is reduced) and bone brittleness. Affected children and adults suffer from repeat multiple bone fractures, requiring hospitalisation and surgery, and often leading to irreversible deformities. They also suffer from short stature and chronic pain.

Why is it important for society?
The BOOSTB4 project is focused on translating fetal-derived mesenchymal stem cell (MSC) transplantation into the clinic as a therapy for OI. During the project we will investigate the safety and efficacy of this innovation in regenerative medicine in the treatment of OI. Successful clinical demonstration of the BOOSTB4 therapy in OI will pave the way for the treatment of many developmental fetal disorders. Curing or decreasing the severity of these congenital diseases will result in life-long benefits for the affected individuals and their families from birth onwards.

What are the overall objectives?
The overall objective of BOOSTB4 is to develop a treatment using stem cells for severe types of OI. The objectives of the project can be summarised in three categories; Clinical, Ethical and Health Economics.

Clinical Objectives
To measure the safety and efficacy of prenatal and postnatal or postnatal fetal MSC infusion (n=30) as therapy for OI (type III and severe type IV).

Primary objective:
The primary objective is to assess safety and tolerability in the woman, fetus and child after prenatal and/or postnatal infusion of four doses of allogeneic human fetal MSC.

Secondary objective:
The secondary objective is to assess the effect of four infusions of allogeneic human fetal liver-derived MSC on:
1. Fracture frequency
2. Time (days) to first fracture after infusion
3. Number of fractures at birth (prenatal treatment group only)
4. Bone mineral density (BMD)
5. Growth (cm and kg)
6. Clinical status of OI
7. Biochemical bone turnover

Exploratory objectives:
1. To study the Quality of Life
2. To study the extent of donor cell engraftment in tissue samples
3. To study paracrine effects of infusions of allogeneic human fetal MSC
4. To study the effect of infusions of allogeneic human fetal MSC on endogenous immune cells
5. To study non-invasive prenatal diagnosis of OI

Ethical objectives
To evaluate the acceptability of fetal MSC treatment, both from the patient and family perspective, as well as from health professionals in the area and from an ethical perspective through:
• Exploring the views and experiences of parents whose child is undergoing fetal MSC transplantation either pre- and/or postnatally and of health professionals who are involved in referring or providing the treatment to understand motivations, expectations and quality of life impact
• To examine current ethical standards and risks associated with prenatal stem cell transplantation

Health Economics Objectives
• To determine if fetal MSC transplantation as standard treatment for OI is cost effective.
• To monitor the resource needed for individuals with severe types of OI and compare to those consumed by matched historical controls.
• To develop a cost analysis model for transplantation of fetal MSC to OI patients.
The BOOSTB4 consortium has, from the beginning of the project, worked on the preparations for submitting the clinical trial application to the authorities. This has involved scientific advisory meetings with the authorities, developing the clinical trial protocol and related documents, finalising the manufacture method of the stem cells, harmonising and setting up necessary procedures at each clinical site as well as composing agreements.
The consortium has also started developing a method for non-invasive prenatal diagnosis of OI. Additionally, the acceptability of prenatal and postnatal stem cell treatment for OI from the perspective of patient and families, health professionals and patient advocates has been evaluated. The work shows that key stakeholders support the application of stem cell therapy for OI.
The MSC treatment proposed here has the potential to reduce fracture rates by half in patients receiving ongoing treatment. The ambition of the BOOSTB4 consortium is to complete our MSC therapy on a large enough cohort to evaluate accurately the potential of this treatment strategy in OI children.
There is currently no cure for OI and the only current pharmaceutical treatments are palliative and fail to sufficiently reduce fracture frequency and does not address the underlying bone brittleness and collagen defect. An individual born with OI is affected throughout their lifetime and the costs of managing the disease are extremely high. Typically, care for these patients requires a large, multidisciplinary team including a neuro paediatrician, physiotherapist, occupational therapist, orthopaedic surgeon, orthopaedic technician, radiologist, geneticist, nurse and dentist. We estimate, conservatively, that the cost of each fracture event in a patient with OI is approximately €15,000. Our early stage indicative costing suggests costs of €10,000 per treatment (four infusions) with MSC therapy. The annual cost savings associated with treatment of patients with the severest forms of OI across the EU, based on a reduction in fracture incidence alone, would be more than €60 million 10 years after introduction of MSC therapy, assuming that each patient has 10 fractures each year, and that this number is reduced to 5 following MSC treatment. If extended to the wider group of patients with OI, these cost savings would increase.

Demonstration of safety and efficacy and the translation of this new technology into clinical practice will likely lead to increased research efforts to apply this technology to other genetic diseases. The results of the BOOSTB4 study will therefore have a large impact on the future treatment of these disorders with MSC.
MSC colony