Care4BrittleBones aims to improve the quality of life of people with Brittle Bones Disease

Finalised projects

Transplantation of mesenchymal stem cells to treat Osteogenesis Imperfecta (Goetherstroem C, Karolinska University Hospital, Stockholm/Sweden. Project end date: 2015)

Researchers from Karolinska University have used stem cells to treat severe OI before and multiple times after birth. One of them is a boy called Adam King, who received significant media attention in 2016 en 2017 here.

The goal of the project was to localize the transplanted stem cells in the bone. Care4BrittleBones supported a part of the research project by enabling a highly specialized technique to be performed on bone material from one of the individuals treated with stem-cells using laser micro dissection.

Result

The project confirmed that the transplanted stem cells have actually reached the bone of the receiving patient and been built in. These results contributed to the principal researcher receiving a 1,6 Mio Research Grant from the European Union (Horizon 2020), which is seen as an area of potential future break through for OI. The name of this multicenter research project is BoostB4. The BOOSTB4 project is focused on translating fetal-derived mesenchymal stem cell (MSC) transplantation into the clinic as a therapy for Osteogenesis Imperfecta. During the project Karolinska and partnering hospital centers (eg University of Cologne/D and University Hospital of Utrecht/WKZ/ Netherlands) 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 OIwould pave the way for the treatment of many developmental fetal disorders. Curing or decreasing the severity of these congenital diseases would result in life-long benefits for the affected individuals and their families from birth onwards. The scientific proof for the efficacy of stemcell treatment is still outstanding at this stage, but enough evidence is there to continue the research in this area at full speed.

As Care4BrittleBones we keep following the development in this area with great interest.

More information is available is availablehere.

Denosumab as an alternative for Bisphosphonates?
(Semler O, University of Cologne/Germany. Project end date: 2016)

Currently children with a moderate or severe type of OI are treated with intravenous bisphosphonates. Due to unknown long-term side effects and the “hassle” with the intravenous application, research is performed to develop alternative approaches to the medical treatment of children with OI. During this study, a special antibody (Denosumab) was used on 10 children to inhibit bone resorption and to stabilize the bones. The aim of the pilot trial, which is co-funded by Care4BrittleBones and is performed at the children´s hospital at the university Cologne, is to assess the efficacy of a therapy with Denosumab in children 5-10 years of age with OI types III or IV.

Result

  • The trial has confirmed the effectiveness of Denosumab for the small cohort of the trial.
  • On average Denosumab leads to significant changes in areal bone mineral density at the lumbar spine.
  • Children under Denosumab treatment show an increase in absolute height.
  • Denosumab appears to suppress bone resorption in children over 10-12 weeks.
  • Denosumab seems to be safe in a one-year treatment course if a sufficient calcium and vitamin D substitution is provided.

More information is available here. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089451/)

Based on these first results the pharmaceutical company AMGEN has now started a 3-year formal clinical trial on a broader cohort of patients around the globe, possibly enabling an alternative option to Bisphosphonate treatment.

Osteogenesis Imperfecta and Fatigue
(Harsevoort A, Isala Clinics/NL. Project end date: 2017)

It seems that people with OI experience more fatigue than the regular population. Therefore the Expertise Centre for OI has investigated if there is a demonstrable link between OI and fatigue, involving 99 adult patients with OI. These insights may help to develop new treatment protocols and thus improve the quality of life for this group of people.

Result

Results from the study confirm the hypothesis that the severity and impact of fatigue in people with OI is greater than in the general healthy population. Interestingly, the score was not very variable between people with different OI types or between people from different gender and age groups.

As people often raise fatigue with OI as a factor that significantly decreases their quality of life, this outcome could be an important indicator that reflects quality of care for OI patients. More information is available here.

Pain Less – OI Youngsters take control
(Barros L, University of Lisbon/Portugal. Project end date: 2016)

Fracture and non-fracture pain can pose a significant burden in the lives of young people with Osteogenesis Imperfecta (OI) and it has been identified as one of the central issues related to their quality of lifeTherefore adequate pain management is essential. Persistent pain in young people is often associated with physical limitations, increased risk of adjustment problems and internalizing symptoms (e.g. anxiety, depression social withdrawal), leading to restricted social interactions and school/work absenteeism. Although medical treatment plays a major role in the management of OI, psychological strategies are critical components of this plan. Even though there is currently no research about the effectiveness of psychological treatment of pain within the OI population, evidence of the positive impact of psychological interventions in young people with chronic health conditions, where pain is a major symptom, is robust. This proposal aimed to develop an online programme to raise awareness and control for OI youngsters pain issues.

Result

The project developed self-management IT-tool based on Moodle – technology. It was applied to a group of Portuguese youngsters with OI. Adherence to the programme has been a challenge. More work would be required to make the tool more interactive and user-friendly for the target group before using it for a larger group of people. The results of the study are being used in other, larger studies looking at pain and OI. This area offers plenty of room for more research in all age groups.

Gene/cellular therapyapproach to treat dominant form of Osteogenesis Imperfecta
(Forlino A, University of Pavia, Italy. Project end date: 2017).

The project will focus on the development of a novel gene-cellular therapy approach for the treatment of the most common dominant forms of the heritable brittle bone disease OI. A validated murine model for classical OI, carrying a single glycine substitution in 1 chain of collagen type I, has been used. A silencing approach has been optimized to stably target the mutant collagen transcript in fibroblast cells that will be dedifferentiated to multipotent iPS cells and then transplanted in utero. Their ability to become osteoblasts in vivo have been stimulated using a specific drug. A success of this therapy in vivo would pave the way for its use in clinical trials using as source of treatment the patients’ fibroblast cells.

Result

The Principal Researcher successfully introduced in a safe genomic murine locus, a single copy of a specific silencing RNA molecule using the innovative genomic scissors CRISPR/cas9. This genetic tool allowed to cut the DNA in a specific location and to insert another DNA sequence, working as drug against the mutation. The silencing RNA (siRNA) introduced was already tested by the researcher as being able to stop the synthesis of the mutated collagen type I chain in the Brtl cells. The effect of this intervention is that the siRNA molecule turns off the mutant allele allowing only the synthesis of normal protein.

Although the success of this approach will need further studies mainly in order to improve the amount of siRNA able to be expressed by the cells, the results will open the possibility to move from the bench to the bedside for the treatment of OI. The design of various silencing molecules specific for the mutations known to cause OI can be easily tested in in vitro systems first, such as in patients cells in a laboratory setting. The ultimate goal is to correct the defect in patient’s cells and to dedifferentiate them to multipotent iPS cells that will then be suitable for transplantation.

Physical rehabilitation for children and adolescents with OI

(Semler O, University of Cologne, and Müller B, Unireha, Center of Prevention and Rehabilitation, Cologne, Germany, in collaboration with an international team of Experts. Follow up lead by Foundation Care4BrittleBones. Project end date: August 2018).This project has been enabled by a grant from AGIS Innovatie Fonds.

The purpose of the project was to collect expert knowledge as well as evidence in the literature regarding physical rehabilitation in children and adolescents with Osteogenesis Imperfecta (OI) in order to develop evidence based recommendations. These consensus statements serve as guidelines for the individual therapist, who needs to adapt them to the needs of each patient. Particular attention must be paid to the severity of the disease in the individual child, as this will influence the therapeutic options and goals. The paper was developed by O. Semler and B. Mueller in collaboration with an expert-group which included 16 representatives (12 physiotherapists, two occupational therapist and two medical doctors) from 14 countries.

Result

The project has resulted in 17 statements ranging across all areas of physical rehabilitation for children and adolescents: Musculoskeletal, spine, self-care and role of upper extremity, infant & development, mobility, post surgery as well as general aspects. The article has been published in open source modus and can be found HERE. The projects results have been overwhelmingly positively received:

  • A webcast was held with physiotherapists, occupational therapists and rehabilitationdoctors from all over the world
  • The guideline is being translated into several different languages including Chinese and Portuguese.
  • Semler has received the Germany Child protection award for his role in this project.

This important topic will continue to receive attention and support. Care4BrittleBones is currently working with the expert team to enable access to various tools and techniques that people with OI can use by themselves or together with their physiotherapist or occupational therapist to achieve the best possible outcomes for their lives through physical rehabilitation.