A multi-omics approach to modeling disease mechanisms in frontotemporal dementia

Frontotemporal dementia (FTD) is a neurodegenerative disease that affects
behavior and personality and ultimately leads to death. There are currently no
means to prevent or cure FTD. Finding a therapeutic intervention for FTD is
challenging due to the pathological and genetic heterogeneity. Pathologically,
frontotemporal lobar degeneration (FTLD) consists of three major subclasses:
FTDL-TDP, FTLD-tau and FTLD-FUS. Genetically, up to 30% of FTD patients are
hereditary, and is most often caused by mutations in the MAPT (FTLD-tau), GRN
(FTLD-TDP), or C9orf72 (FTLD-TDP) genes. The remaining 70% of patients
(non-hereditary or sporadic FTD) seem to be due to a combination of unknown
genetic and environmental factors. Underlying pathology in sporadic FTD
patients cannot be determined based on the clinical picture and can be seen in
all three pathological subclasses. We hypothesize that unravelling the
diversity of molecular pathways within these subtypes, and identifying
potential common denominators by integrating clinical, pathological, molecular
and cellular knowledge of iPSC-derived neurons and brain tissue of
well-phenotyped FTD patients will accelerate drug development for these
disorders.
To understand the implications of our findings, we need to approach proteins
and their pathways in vivo. An innovative way to validate our preliminary
findings is to study disease mechanisms in FTD patient derived induced
pluripotent stem cell (iPSC) lines. Importantly, contrary to the use of animal
models, iPSC technology enables research in all subtypes of FTD.

To overcome the heterogeneity dilemma that hampers drug development, we propose
a translational within-subject approach that integrates clinical, pathological,
and molecular/cellular data of induced pluripotent stem cells (iPSC) derived
neurons and brain tissue of the same donor to identify molecular profiles and
(novel) drug targets for personalized treatment strategies.

Our specific objectives are to:
1) Collect clinical, pathological and biochemical data of FTD patients to
define the phenotype of the patients in detail
2) Identify and validate skin biomarkers for FTD
3) Reprogram fibroblasts towards iPSCs, characterize the iPSCs and generate
welldefined iPSC-derived neuronal cells that can be used for FTD research
4) Identify molecular (proteomics) and cellular (cellomics/microscopy) profiles
of postmortem
brain tissue and iPSC of the same FTD patients to aid in identification and
validation of druggable targets for personalized therapeutic strategies.

We will collect skin biopsies of whom pathological confirmation will be
available via the Netherlands Brain Bank and validate skin biomarkers. In
parallel, we will prospectively collect skin biopsies from well-phenotyped
sporadic patients who gave consent to future brain donation, and patients with
a genetic form of FTD. We will generate well-defined iPSC-derived neurons.
Using advanced -omics techniques we will define molecular profiles of the iPSC
and braintissue samples of the same donor. This will enable us to identify and
validate druggable targets.

The patients participating will undergo a skin biopsy of 3 mm. Risks related to
the skin biopsy are occurrence of a hemorrhage, infection and a minimal chance
for scarring. The patient will get offered a local anesthetic to reduce the
pain associated with the biopsy. To minimize the chance for complications, a
detailed history with regard to medications that can cause prolonged bleeding,
increase risk of infection or delay healing will be checked. The chance for the
occurrence of an infection will be minimized by following standardized biopsy
protocol and execution of the biopsy will only be performed by a physician or
trained and certified nurses. The biopsy location will be along relaxed skin
tension to optimize healing and minimize scarring
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728909/) . The burden will be
kept minimal. The study has to be performed in a population of FTD patients and
is therefore group related. The outcomes of our project will eventually be
beneficial to all FTD patients of all subgroups. In particular this project
makes sense for the 80% of sporadic FTD cases, who have been relatively
neglected in FTD fundamental research. There has been no research using iPSC in
sporadic FTD so far. The research that we aim to perform will create great
opportunities for the international research community as well as pharma. Since
drug development takes several years after completion of this project, there
will be no direct benefit for patients currently suffering from FTD. However
when successful, the benefit will be clear for future FTD patients. This
project is the stepping stone for the assay development and drug testing that
is to the standards of clinical screening. A future advantage is that we have a
large and trial-ready clinical FTD cohort available that has been deeply
phenotyped using clinical, biological, neuroimaging, and genetic markers.