De novo GoF mutations in the SCN2A gene cause an early-onset, Dravet syndrome-like epileptic encephalopathy (EE) with severe intellectual disability and increased risk of sudden epileptic death.
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WP2 will apply cutting-edge models and discovery technologies with patient-derived data to develop new therapeutic modalities (small molecules, natural compounds, repurposed drugs) to target loss-of-function (LoF) and gain-of-function (GoF) mutations causing severe multi-systemic disorders in children and adults.
LoF mutations reduce or abolish protein function and represent the most common cause of genetic disorders. We will target severe multi-systemic metabolic diseases with a combination of cutting-edge approaches to restore cellular function downstream of the primary defect.
Autosomal recessive methylmalonic aciduria determine the accumulation of toxic metabolites and reactive oxygen species which cause mitochondrial dysfunction. Symptoms include acute metabolic decompensation leading to early death, chronic kidney disease with renal failure, and neurological sequelae.
These two X-linked diseases affect the endolysosomal compartment sustaining the re-absorptive capacity of cells lining the proximal tubule of the kidney. They are characterized by massive losses of solutes in urine leading to life-threatening metabolic complications, kidney stones and chronic kidney disease.
Hemophagocytic Lymphohistiocytosis (HLH) includes a group of genetic disorders of lymphocyte cytotoxicity predisposing to a severe multisystem inflammatory syndrome. Immune stimulation is poorly controlled, leading to excessive activation of T cells and macrophages and a life-threatening cytokine storm. The symptoms often appear within the first few months or years of birth and are much the same as those of other childhood illnesses, making it hard to diagnose.
GoF represent a major therapeutic challenge, particularly when they are private, occur de novo or lead to early onset diseases. We will use CRISPR-Cas base editing and small molecules to target disease-causing mutations at the DNA and protein levels.
De novo GoF mutations in the SCN2A gene cause an early-onset, Dravet syndrome-like epileptic encephalopathy (EE) with severe intellectual disability and increased risk of sudden epileptic death.
Many rare diseases are caused by dysfunctional organelles or trafficking that impair cellular function and cause severe tissue damage with devastating clinical manifestations. We will use small molecule-based modulators, repurposed drugs, and RNA-based gene editing to develop novel treatments.
