Primary1) Identify a selection of Child Brain Lab assessments that can serve as clinically relevant and feasible outcome measures for an anticipated gene therapy intervention trial in children & adults with calcium-related synaptopathies2)…
ID
Source
Brief title
Condition
- Neurological disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint 1
Feasible outcome measures for follow-up & intervention trials
Identify a minimum of four CBL assessments that can capture patient*s main
clinical symptoms up into adulthood.
Our pilot data -using both caregivers and health care professionals as a
source- indicates that the following measurements hold promise:
o EEG background pattern (spectral analysis for the alpha, beta and theta bands
during resting and upon social and non-social videos. Spectral analysis is a
standard method for quantification of the EEG) and has been shown to be altered
in children with neurodevelopmental disorders [e.g. Hipp 2021, Frohlich 2019].
o Score on eye-tracking tasks (social paradigms) #
o ERP (auditive Event-Related Potential) #
o Communication skill measures
o OCT (retinal nerve layer thickness)
o Motor function (standing balance, gait deviation index)
o 24-hour movement behavior including sleep (activity tracker)
o Growth parameters (including head circumference), body composition and facial
shape (3D photography measures)
*For the proof-of-concept cohort, we expect adult patients to have a
developmental age younger than 4 years. However, assessments can be adjusted to
any developmental age using the standard CBL protocol.
# Measurements performed in combination with EEG
Primary endpoint 2
Create detailed and standardized natural history data of adults with
intracellular calcium-related synaptopathies to be used for primary aim 1 and
secondary endpoint 2, in addition to provide better counseling of caregivers
about prognosis and for the design of intervention studies. Once we have
obtained a core set of assessments, we can expand this to other CAMK2 expertise
centers around the world. Together with the parent organization, we are
focusing on building a network of expertise centers, starting with North
America.
Secondary outcome
Secondary endpoint 1
Create shared and disease-specific developmental curves with relevant and
meaningful outcomes across four domains (cognition, behavior & language,
neurophysiology, brain & craniofacial structure, and motor development) in
children with intracellular calcium related synaptopathies, both from
well-established and validated parameters in addition to newly developed
parameters. This requires integration of parameters collected in time. We will
start with outcomes in the domains cognition, behavior, language, and sleep.
Secondary endpoint 2
Develop biomarkers from neurophysiological, gait analyses, MRI metrics, 3D
photogrammetry, and OCT data in collaboration with researchers from TU Delft
that can be used to predict long term development. This will be part of the
larger CBL initiative to use machine learning algorithms (both classic and more
advanced neural network-based methods) to identify new biomarkers. The
multi-domain nature of the data (OCT, EEG, patient reports, etc.) will allow to
apply multi-modal types of AI algorithms, which will be trained on integrated
information from different measurement modalities.
Background summary
The Pediatric Brain Center (PBC) is a collaboration of medical professionals
and researchers in the Erasmus MC - Sophia Children*s Hospital who are involved
in the clinical care for and research in children with conditions of the brain,
nerves, senses and limbs. To improve family participation, quality of care and
facilitate research and trials, the Child Brain Lab (CBL) has been established.
The CBL is designed as a functional lab enabling standardized follow-up in
relevant and meaningful domains for natural history building and for
identification of biomarkers for prognosis and treatment evaluation. The CBL
began actively recruiting patients in the summer of 2023 (MEC-2022-0606),
including children with ultra-rare congenital brain conditions who are being
treated by clinicians at the NFU-accredited ENCORE expertise center. In the
current protocol, we seek approval to include (inter)national patients over the
age of 18 years as this adult cohort offers crucial insights into the natural
history of these (ultra) rare conditions and adult patients are eligible for
gene-therapy approaches. The submitted protocol has only mild adaptations to
the original protocol of the CBL (NL82466.078.22 / MEC-2022-0606).
One of the patient groups currently being recruited by ENCORE for CBL
participation consists of children with a neurodevelopmental disorder caused by
mutations in intracellular calcium-signaling genes. These disorders are
collectively known as calcium-related synapthopathies, with CAMK2 syndrome
being one example. ENCORE has extensive expertise in this specific synaptopathy
and established the world*s only center of expertise in 2019. Over the next
five years, our neuroscientists aim to develop a personalized ASO gene
therapy-based treatment, with a proof-of-principle focus on CAMK2 patients with
gain-of-function (GOF) mutations, specifically targeting the Pro139Leu and
Thr286X variants. This work is funded by the Dutch *Hersenstichting* (number
grant application: DR-2023-00429) and *Dioraphte* (number grant application:
116320) foundations and is in close collaboration with the parent foundation:
CAMK2 therapeutics network (https://www.camk2.org). In parallel, we as a
clinical team are focused on identifying reliable and feasible clinical outcome
measures to assess whether the ASOs can indeed significantly improve patients'
quality of life. To accomplish this goal, we are utilizing the CBL facility.
Given that CAMK2 synaptopathy is an ultra-rare condition, with an even smaller
subgroup of patients having these specific variants, international patients are
also invited to visit the CBL at Erasmus MC. Under the Child Brain Lab protocol
(NL82466.078.22), permission was obtained to allow children aged 0-18 years to
participate in the study. In the current protocol, we seek approval to include
(inter)national patients over the age of 18 years. As patients with CAMK2 GOF
mutations are on the very severe end of the clinical spectrum with profound
intellectual disability, wheel chair dependance and no speech, assessments in
line with their developmental age are deemed appropriate. Moreover, our
fundamental research team showed that adult restoration of CAMK2 in the brain,
cures mice with CAMK2A-dependent NDD, hence an age-limited treatment window
seems not applicable.
Study objective
Primary
1) Identify a selection of Child Brain Lab assessments that can serve as
clinically relevant and feasible outcome measures for an anticipated gene
therapy intervention trial in children & adults with calcium-related
synaptopathies
2) Collect detailed and standardized natural history data of adult patients
with calcium-related synaptopathies. We will start including CAMK2 patients on
the severe end of the clinical spectrum as these will be the primary target for
disease modifying (gene) therapies.
Secondary
1) Create shared AND disease-specific developmental curves in patients with
intracellular calcium-related synaptopathies.
2) Use advanced data-analyses/statistical techniques and AI to identify early
biomarkers that help predict long term development across intracellular calcium
related-synaptopathies.
Study design
Observational cross-sectional study.
Study burden and risks
The burden of participating in the CBL test circuit is a time investment of 3
days in total extended by the time needed to travel to the Netherlands. Tests
itself are non-invasive and not painful. However, due to their underlying
genetic condition with intellectual disability, unique behavioral
characteristics, and the absence of speech means that this patient group may
respond differently to measurements than neurotypical individuals. Therefore,
the travel and visit to the children's brain lab may be perceived as stressful
or anxiety-inducing. To minimize negative experiences, caregivers can receive
tailored counseling to prepare their child for the visits. Significant
expertise has been gained within ENCORE (Angelman Syndrome) and through the
pilot tests of the children's brain lab circuit. Moreover, we have had positive
experiences with a similar NDD patient group (GRIN, n = 15) so far. During each
measurement, the tester will evaluate whether the next measurement is feasible
and acceptable, in close consultation with the family. We will terminate the
measurement if the participant shows signs of anxiety, distress, or objection.
Patients carrying CAMK2B-p.(Pro139Leu) and CAMK2A-p.(Thr286X) variations will
directly benefit from results. As this is a proof-of-concept study, we can and
will extrapolate our results and methods to other CAMK2 mutations as well as
other synaptopathies. Moreover, non-gene therapy interventional trials can
benefit from study results also. F.e. tailoring alternative speech-language
support, adaptation of drug treatment for symptom relief for common behavioral
and sleep problems and/or epilepsy.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
- Age >18 years old
- Genetic testing confirming a pathogenic variation (using international ACMG
criteria) resulting in an intracellular calcium-related synaptopathy (CAMK2,
GRIN, GRIA).
For the proof-of-concept study we start recruiting patients with a mutation in
either the CAMK2B (Pro139Leu) or CAMK2A (Thr286Xvariants) gene.
- Able to provide written informed consent by a biological parent and/or legal
representative.
- Caregivers are sufficiently proficient in either Dutch, English, French or
Spanish in order to complete questionnaires.
Exclusion criteria
- Unable to understand or comply with the test circuit at the discretion of the
treating physician (this concerns the parents of the patients as all are
incapacitated).
- Patients with more than 1 genetic diagnosis.
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| CCMO | NL88035.078.24 |