Therapeutics for metabolic diseases
14 important questions on Therapeutics for metabolic diseases
Conclude with the learning goals in mind:
✓ To gain insight into inherited neurometabolic disorders
✓ To delineate different therapeutic approaches
✓ To discuss a clinical case vignette
✓ Emma Center for Personalized Medicine
✓ Valorisation via 3FM Serious Request
...
The case vignette is about the pyridoxine dependent epilepsy. Treatment with supplements and knockout of the AASS enzyme.
Emma center focusses on the 4P's and collaborations also with the patient.
What type of genetic disorders are metabolic disorders? Leads to..?
Disrupted biochemical reaction pathway; pathway that is important for energy production.
What are implications of the diseases? (4) Name 3 symptoms. 2 organs mostly affected.
- Energy deficiency & Shortage of building blocks
- Accumulation of (toxic) substances
- Children & adults; any organ(s) can be affected
- Static but more often progressive symptoms
- epilepsy (neurometabolic)
- developmental delay
- movement disorders
- Brain (uses energy the most)
- Gut
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What is a key characteristic for metabolic disorders for therapy designing?
What are the numbers
- inherited metabolic diseases
- how many in the screeningsprogram
- % neurometabolic
- % diagnostic success
- % treatment succes
20
60%
70%
15%
What are different therapeutic approaches for IMDs?
Medicine => supplement, intervene on the pathway
Gene therapy
What is P4 medicine and how does this relate to IMD?
- Predictive: precise molecular diagnosis
- Preventive: disease modifying + targeted therapies
- Participatory: patient as partner
- Personalized: phenotype and function first + personalized outcomes
There are different kinds of interventions. From simple to innovative. Based on the pathway that is impaired. Name examples.
2. Supplement tyrosine for example => in PKU
3. Other enzymes that potentially can do the same job
4. Provide a co-factor -> for transformation of molecules.
5. Hydroxylate enzyme -> to transform one amino acid into another.
6. Transplant an organ: for example, liver => too risky for PKU (phenylketonurie)
7. Stem cell, CRISPR.
What is the difference between RNA therapy and DNA therapy?
provide the correct RNA => but it is a very temporary replacement so you must repeat it
Gene therapy still has a long way to go. RNA therapy is more useful at the moment
Risk of DNA therapy is overcorrecting: meaning that gene replacement or gene silencing leads to an unphysiological (maybe neurotoxic) over- or underexpression of the healthy (endogenous or exogeneous) allele in a proportion of cells.
Currently difficult to predict expression levels when you deliver gene therapy.
What is the epidemiology of neonatal metabolic epilepsy? % treatable?
20% is treatable
What is the cause of pyridoxine-dependent epilepsy? (3)
- Higher levels of P6C cause inactivation of PLP (B6). PLP is the active form of B6 => you need this to prevent seizures
- Deficiëntie of enzym L-2-aminoadipate-6-semialdehyde (α-AASA)-dehydrogenase leads to increased α-AASA
- Higher levels of pipecolic acid
P6C and AASA => are neurotoxic; intellectual disability
What is an example of (adjunct) therapy for pyridoxine-dependent epilepsy (PDE)?
- protein restricted diet (no intake of lysine) & arginine supplementation to compensate for lysine
- reduces neurotoxic metabolites
- clinical effects…
What was the conclusion of the diet and supplements study? => clinically relevant
Describe a second example of adjunct therapy? How do we test this therapy?
Animal models: knockout model
Human models: neuronal models (organoids)
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