Integrated Prospective and Retrospective Observational Study to Characterize Biomarkers and Disease Progression in Patients with Pelizaeus-Merzbacher disease

Neurons are a special type of cell in the brains and spinal cord that transmit
and receive electric signals (impulses) throughout the central nervous system.
Neurons are covered in myelin. Myelin serves an incredibly important function.
It protects the axon and allows an impulse to get from one neuron to another.
The protein called *proteolipid protein 1* (PLP1) plays an important role in
the formation of myelin. In PMD the protein PLP1 has abnormalities and causes
little or no myelin to be formed. This results in little, if any, impulse
making it to the next neuron, which causes problems in the nervous system of
the patient.

Primary objectives:
To prospectively assess longitudinal changes in Proteolipid Protein 1 (PLP1)
and additional disease-related biomarkers in cerebral spinal fluid (CSF) and
blood and evaluate their utility in support of the development of therapies for
PMD.

To prospectively assess longitudinal changes in neuroimaging parameters
relevant to PMD, including but not limited to myelination and white matter
atrophy.

To prospectively assess longitudinal changes in performance on clinical, and
patient and caregiver-reported outcome assessments to inform development of
therapies for PMD.


Secondary objectives:

To characterize health services utilization and economic and disease burden for
the patients and caregiver(s).

To perform a retrospective chart review of the patient*s medical history and
family history to characterize the natural history (NH) of PMD since birth.

To identify associations that may be potential predictors of pathological and
clinical progression in PMD.

This is a multi-center, non-randomized, non-interventional integrated
prospective and retrospective study in participants with PMD who are able to
undergo general anesthesia or conscious sedation to collect fluid biomarkers
(CSF and blood), neuroimaging, and clinical assessments to be used in support
of the development of therapies for PMD.
Up to 5 sites worldwide will participate in this study.
Approximately 20 participants who have a diagnosis of Pelizaeus-Merzbacher
Disease with genetic confirmation of PLP1 duplication will be enrolled into
this study.

Prospective Study
Each participant will undergo a minimum of 2 CSF collections and neuroimaging
procedures, at the Baseline visit and Week 53 visit. A third CSF collection
and neuroimaging procedure may be performed at the Week 106 visit if feasible.
Prior to each CSF collection and neuroimaging procedure, participants and their
caregivers will complete standardized clinical, patient and caregiver
assessments, conducted over multiple calendar days (if needed). A subset of
patient and caregiver reported outcome assessments will be administered
remotely approximately every 6 months.
Participants not completing at least 2 CSF collection or neuroimaging
procedures may be replaced. Up to 40 participants may be enrolled.
Twenty-four (24) hours following each CSF collection procedure, follow-up
contact (via telephone call or in person) from the Study Center will be made to
the participant's caregiver for a safety assessment.
The study duration for each participant will be up to 26 months.

Retrospective Study
Each participant*s medical and family history data will be collected
retrospectively from available medical notes and charts, from birth up to the
end of the study period. Data collected may include but is not limited to
medical and treatment history, family history, age at onset and diagnosis,
clinical assessments, hospitalizations, procedures, genetic diagnoses, and
laboratory assessments. These data will be collected by qualified site
personnel with expertise in PMD and entered in the study database during the
prospective study. The retrospective study will only collect data from
participants registered in the study.

The patient will need to visit the study center 4 times during the whole study,
which will last 26 months. These are a screening visit and 3 visits during the
study, in week 1, 53 and 106.

Blood draws:
Blood draws will be performed 4 times at the visits at the study center
(screening, week 1, 53, 106). At every occasion 2-6 ml blood will be drawn,
depending on the weight of the child. In total the maximum volume for blood
draws will be approximately 47ml during the whole study.

MRI / MRS:
At studies visits in week 1, 53 and 106 MRI/MRS will be performed on the
patient.

Lumbar puncture for brain fluid collection:
At least 2 lumbar puncture will be performed during the whole study to collect
brain fluid. These lumbar punctures will be performed during the study visit in
week 1 and 53. In week 106 an additional optional lumbar puncture might be
performed.

ECG:
During the screening visit an ECG will be performed. No further ECGs are
planned during the study.