Inherited Metabolic Disorders: Overview of Personalised Therapies Flashcards
What are Inherited Metabolic Disorders (IMD)?
- definition
- 4 issues/ themes to consider
— also known as inborn errors of metabolism — are heritable, or genetic, disorders
–> DNA defect leading to disrupted biochemical reactions or pathways
4 issues:
- Energy deficiency & Shortage of building blocks
* Accumulation of (toxic) substances
* Children & adults; any organ(s) can be affected
* Static but more often progressive symptoms
What are Inherited Metabolic Disorders?
- symptoms
- common treatment
Symptoms:
- In young infants include –> apnea, lethargy, poor feeding, tachypnea and vomiting
Common Treatment:
- enzyme replacement, gene transfer and organ transplantation
- Effects vary from improvement, stabilisation, prevention, and unclear
Shortage of Energy leads to 3 main issues
1.
2.
3.
- Brain
- Liver - toxicity
- Heart
What makes IMD hard to diagnose?
vide variety of symptoms
Why is important to diagnose/treat IMD early?
- Window of opportunity
- damage when too long untreated
Therapeutic Intervention
- Limited intake of substrate
- Supplement product
- Stimulate alternative pathway
- Provide co-factor
- Supply enzyme
- Transplant organ
- Gene therapy
Nutritional Therapy
most dietary treated IMD are cause by the accumulation of substances that are toxic or affect normal function, or the effects of reduced ability to synthesize essential compounds.
Conditions may be treated by adaptations to protein, fat, and carbohydrate intake, with supplementation with synthetic or modified protein, amino acids, triglycerides, or carbohydrate sources.
LARS1 deficiency
- LARS1 = Leucyl-TRNA Synthetase 1
- a Protein Coding gene –> autosomal recessive disorder
- cytoplasmic leucyl-tRNA synthetase enzyme, –> catalyzes the ATP-dependent ligation of L-leucine to tRNA(Leu) during protein translation
- Diseases associated with LARS1 include Infantile Liver Failure
Symptoms
- acute liver failure
- anemia, renal tubulopathy, abnormal brain MRIs, failure to thrive, developmental delay, and seizures
What is the catch 22 in involving pharma in drug discovery?
+ they pay for the trials and costly discovery
- request high prices for final product
What are the issues with using amino-acids as treatment for LARS1?
- low evidence level
- hard to come by high quality amino acids
- optimal dosage unknown
- lack of approval and reimbursement
What is an N-of-1 trial design?
- N-of-1 trials in clinical medicine are multiple crossover trials, usually randomized and often blinded, conducted in a single patient.
- patient is their own control
- meta-analysis of multiple N-of-1 trial yields evidence level 1
How long (ca.) does de novo drug discovery and development last – and what stages does it entail?
> 10 years
- 4 to 8 years: Basic Study, Drug Design, Experiment in vitro, Experiment in vivo
- 5 to 7 years: Phase I to III Clinical Trials
- 1 to 2 years: Drug Registration
What are disadvantages of De novo drug discovery and development?
- long duration
- expensive
- low success rate
How long (ca.) does drug repurposing last – and what stages does it entail?
< 5 years
- Drug is already discovered
- merely testing in different disease
What are the advantages of drug repurposing?
- known drug safety
- reduced pharmacokinetic uncertainty
- shorter duration
- more affordable
