An exploratory, open label, multiple dose, multicentre phase I/II trial evaluating safety and efficacy of prenatal and/or postnatal infusion of allogenic expanded fetal mesenchymal stem cells for the treatment of severe Osteogenesis Imperfecta compared with historical and untreated prospective controls.;In the Netherlands patients will not be treated. Retrospective and prospective control patients will be included

Osteogenesis Imperfecta (OI), or brittle bone disease, is a debilitating
congenital disorder with prenatal onset leading to osteopenia and bone
brittleness. Affected children and adults suffer from repeat, multiple bone
fractures, requiring hospitalisation and surgery, often leading to irreversible
deformities in severely affected individuals. Diagnosis is usually made at the
routine fetal anomaly ultrasound scan performed mid-pregnancy in countries in
the European Union (EU) during pregnancy, where the characteristic shortened
long bones and fractures are already present and detectable.

OI is a group of genetic disorders caused mainly by >1,400 different dominant
and >150 recessive mutations. One child among 10-20,000 is born with OI and
mutations in the collagen genes resulting in abnormal collagen microfibril
assembly are most common in the moderate/severe types. The major clinical
manifestations are atypical skeletal development, osteopenia, multiple painful
fractures and short stature, but >50% of OI individuals also suffer from
brittle teeth, hearing loss and hypermobile joints and there is also a higher
risk of heart valve insufficiency, aneurysms and bleeding and coagulation
deficiencies throughout their lifetime. OI presents in a clinically
heterogeneous manner, ranging from the mild type I that may only become evident
in adulthood to the perinatally lethal type IIA/C. Life expectancy is not
affected in milder OI types but may be shortened for those with more severe
types. Type III OI is the most severe form that is compatible with survival
into adulthood. Individuals affected by OI type III may experience hundreds of
fractures in a lifetime. Type III is the most severe forms in children
surviving the neonatal period, manifesting with extremely short stature and
multiple painful fractures, spinal deformities and kyphoscoliosis predisposing
to premature respiratory death in the most severely affected cases. However,
most commonly OI presents in childhood with multiple fractures after little or
no trauma (type I/mild type IV). OI type IV results in reduced stature and is
moderately deforming.

Whole-body dual energy X-ray absorptiometry (DXA) images of adults with OI
shows the wide spectrum of skeletal manifestations in OI; from the mild
abnormalities in type I OI to the severe deformities in type III OI. The
arrowheads indicate orthopaedic rods in the long bones and the arrows indicate
fragmentation of the epiphyseal growth plates (*popcorn epiphyses*). One
individual with type IV OI underwent amputation of both legs owing to multiple
fractures.

There is no cure for OI, with the only current pharmaceutical treatments being
symptomatic and inadequate in reducing long bone fracture frequency and failing
in addressing the underlying molecular pathology, the bone brittleness and
collagen defect. Treatment is aimed at increasing overall bone strength to
prevent fractures and maintain and/or increase mobility. This is accomplished
with physical therapy to strengthen the muscles and improve mobility and
life-long orthopaedic interventions such as the insertion of rods in the long
bones to correct bone deformities. Bisphosphonates (BP) are used to reduce bone
resorption and increase bone mass. However, two recent meta-analyses of
randomised trials on BP treatment for OI did not demonstrate improvement in
fracture rates, reduction of pain or functional mobility.There is also growing
concern regarding the role of BP in causing impaired bone remodelling in these
children, which may be counterproductive. A study has demonstrated that
individuals with OI are in need of most care at age 1-14 years with a high
demand on hospital services [12], which shows the importance of taking action
early against this destructive disease. Thus, new treatment modalities are
needed. Infusion of stem cells that produce healthy collagen and that can
engraft into damaged bones and support the development of new normal bone is an
approach that holds great promise for OI individuals, and as described below,
prenatal treatment may be even more efficacious than postnatal treatment.

Across Europe, prenatal diagnosis of severe OI is commonly suspected at the
routine anomaly scan conducted around 18-20 weeks of gestation. A prenatal
diagnosis of OI cannot be confirmed without a molecular diagnosis from fetal
genetic material obtained following amniocentesis or chorionic villus sampling.
The result is often not available before 21-22 weeks of gestation, which is a
common deadline for termination of pregnancy in some countries. Couples, even
if they might consider termination of pregnancy as an option, may not therefore
be offered the choice. Prenatal therapy using fetal mesenchymal stem cell (MSC)
infusion gives couples a third option, to treat the fetus before birth. In
addition, a significant proportion of parents do not want to terminate a
pregnancy, but want to improve the situation of their child irrespective of the
severity of the fetal disease detected. Such couples could soon be offered
prenatal therapies. Finally, prenatal treatment may have clinical advantages
over postnatal approaches (see section 4.3 of the protocol).

This study has been transitioned to CTIS with ID 2023-504593-38-00 check the CTIS register for the current data.

The aim of this trial is to infuse multiple doses of human 1st trimester
liver-derived MSC for the treatment of severe OI to determine the safety,
tolerability and clinical effectiveness of prenatal and/or postnatal infusion
of same-donor fetal MSC. The trial will provide data to support the future
clinical development and commercialisation of this therapy. We will also assess
the potential of non-invasive methods of prenatal diagnosis for OI for improved
clinical translation of prenatal therapeutic approaches. The trial will be
conducted in compliance with the Clinical Trial Protocol, Good Clinical
Practice (GCP), the Declaration of Helsinki and the applicable regulatory
requirement(s).

Severe OI is an incapacitating inherited chronic disease with no curative or
sufficiently effective treatment. OI causes damage already in fetal life.
Therefore, it is desirable to introduce treatment as early as possible before
additional pathology occurs and at a time of rapid skeletal development. MSC
may ameliorate OI, and can be administered before and/or after birth,
suggesting a potential treatment of OI. Persons with severe types of OI are
seriously ill and suffer from multiple disabilities and chronic pain through
their lifetime. A prenatal or early treatment of this severe disorder would
therefore be of benefit. Even though a single prenatal infusion may not be
clinically sufficient for permanent improvement, a prenatal infusion approach
is still justifiable since the immunological naïveté of the fetus may allow for
the development of immune tolerance towards the donor cells rendering postnatal
booster infusion more efficient. Pre-clinical studies show that early treatment
either in utero or in neonatal mice is more effective at treating OI than later
treatment [38, 39]. In addition, as the infusion is given into the umbilical
vein in the fetus, it will bypass the pulmonary circulation via two fetal
shunts, the ductus venosus and the foramen ovale. This ensures that the infused
MSC go directly into the systemic circulation and can then home directly to the
bones. MSC infusion after birth is performed into a peripheral vein, with many
MSC becoming trapped in the microcirculation of the lungs [40-44], before fewer
MSC reach the systemic circulation.

The rationale for repeated infusions (four infusions per child) of same-donor
MSC postnatally is based on the clinical data from the published studies on
stem cell transplantation in OI, where the effect diminished after 3-6 months
after transplantation [17, 45, 46], and on our own experience and data [18,
19]. If the child*s developing bones repeatedly are strengthened early in life
there is a good chance that the OI phenotype will be less severe also later in
life.

The dose of fetal MSC for prenatal and postnatal infusion is approximately
3x106 cells/kg bodyweight. The doses refer to the total number of live cells in
the preparation after thawing. The dose is based on our available data on
safety and efficacy from pre- and postnatal infusion in fetuses, infants and
children [17-19] and our unpublished data on experimental treatment of OI,
Gaucher Disease type 2 and bronchopulmonary dysplasia (see the Investigators
Brochure, IB).

First trimester liver has been selected as the starting material for the IMP.
This is because of the superior characteristic of these isolated cells in
comparison to other cell sources. MSC derived from fetal tissues are found at a
higher frequency with greater colony-forming capacity, have longer telomeres
and a superior proliferative and differentiative capacity [30, 31, 33, 47].
Fetal MSC are also more osteogenic compared to MSC from adult sources [32, 34,
48]. Fetal MSC have, similar to adult MSC, a low immunogenic profile [26, 29].
Lastly, in prenatal transplantation it has been demonstrated that it is better
to use fetal than adult cells. Fetal liver cells had a 10 times higher
competitive engraftment advantage compared to adult bone marrow cells, and
fetal liver cells repopulated 8.2 times better than adult bone marrow cells
after prenatal transplantation [49].

Successful clinical demonstration of BOOSTB4 therapy with fetal MSC in OI will
pave the way for the treatment of many developmental fetal disorders.
Decreasing the severity of these congenital diseases results in life-long
benefits for the affected individual from birth onwards, thus providing many
decades of quality-adjusted life years. For the parents, providing treatment as
soon as a prenatal diagnosis is made rather than waiting until after birth may
allay some of the anxiety associated with the diagnosis. It can be concluded
that the overall risks (mainly tumour formation, which is calculated to be low
and risks associated with the infusion procedure, which is 0.1-1%) posed to the
subjects in this trial are low and do not outweigh the potential benefits (see
section 16.3 for more information).

In the Netherlands only the historical and prospective controls with OI type
III or severe type IV will be included

The trial is an exploratory, open label, multiple dose multicentre phase I/II
trial of allogeneic human fetal MSC infusion for the treatment of OI type III
or severe type IV compared with historical and untreated prospective
controls.The trial is divided into a 2-year treatment period (period 1)
followed by a non-interventional follow-up period until 10 years after
inclusion (period 2). Subjects can be enrolled during the initial 3 years of
the treatment period. The maximum treatment time for each subject is 20 months.

Two groups of 30 subjects in total will be enrolled in the trial and these
groups will be compared with a third historical and/or prospective untreated
control group. The subjects are included in the two groups based on
availability and subject to practical issues:
1. Prenatal group: pregnant women whose fetus has been diagnosed with OI type
III or severe OI type IV prenatally on ultrasound findings, and confirmed using
molecular analysis of fetal genetic material as having a pathogenic collagen
mutation
2. Postnatal group: infants diagnosed with OI type III or severe OI type IV on
clinical findings, and confirmed using molecular analysis of fetal genetic
material as having a pathogenic collagen mutation
3. At least 30 historical and prospective controls with OI type III or severe
OI type IV on clinical findings, and confirmed using molecular analysis of
fetal genetic material as having a pathogenic collagen mutation

Persons with OI will be recruited from across Europe from three clinical sites
in Sweden, the United Kingdom and the Netherlands. Subjects in the prenatal
group will be included in the trial before birth between 16 and 35+6 weeks of
gestation and subjects in the postnatal group can be included in the trial at
three set time points after birth (4, 8 and 12 months of age), and receive
treatment at the time points 0, 4, 8, 12 months after inclusion. All time
points are defined as ± 1 month.

Subjects in the prenatal group will receive the first treatment prenatally
(between gestation weeks 16 and 35+6) and will then be treated and evaluated at
4, 8, 12 months of age and follow-up will be performed 6 and 12 months after
the last infusion. Subjects in the postnatal group will be included and receive
the first treatment at 4, 8 or 12 months of age (option 1, 2 or 3) and then be
treated and evaluated at 4, 8, 12 months after inclusion and follow-up will be
performed 6 and 12 months after the last infusion (period 1) All infusions are
performed with same-donor cells for each subject. After the follow-up 12 months
after the last infusion, all subjects (all children and the mothers where
infusion was performed during pregnancy) will be followed for at least 10 years
after inclusion in the study (period 2).

Women whose fetus underwent infusion of MSC prenatally will be followed with
maternal blood sampling up to 4 months after the birth of their child to
analyse for transfer of donor cells and development of donor specific
antibodies. After this point, no blood samples will be taken unless clinically
indicated. Women taking part in the current trial will be informed that they
should notify the BOOSTB4 trial centre and their general practitioner in the
event of a future pregnancy.

In short: This will be a multi-centre, open label, multiple-dose, phase I/II
trial of allogeneic human fetal MSC infusion for the treatment of OI type III
or severe type IV compared with historical and untreated prospective controls.

No intervention for Dutch historical and prospective controls.

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