Inherited metabolic diseases: 2022 overview of personalized therapies Flashcards
How can inherited metabolic disorders be defined?
A large group of monogenic disorders, caused by defects in the DNA leading to disrupted biochemical reactions or pathways.
What are characteristics of inherited metabolic disorders?
- Energy deficiency and shortage of building blocks
- Accumulation of (toxic) substances
- Any organ(s) can be affected
- Static but more often progressive symptoms.
Why should we care for rare neurometabolic disorders?
- Symptoms are often severe
- Epilepsy, developmental delay, regression, intellectual disability, movement disorders, neuropathies, psychiatric/behavioral.
- Window of opportunity
There are different ways metabolic disorders can be treated, specifically by interveining in the metabolic pathway.
Name ways you can interveine here.
- Limit intake of the substrate
- Supplement the product
- Stimulate an alternate pathway
- Provide co-factor
- Supply enzyme
- Transplant organ
- Gene therapy
See picture. This girl was diagnosed with a LARS1 deficiency. This gene encodes a cytosolic leucine-tRNA synthetase and is part of a family of related genes known as Aminoacyl-tRNA synthetases (ARSs). What is the main function of ARSs genes?
Loading tRNAs with cognate amino-acids to enhance translation.
What is a possible hypothesis for the pathophysiology of ARS1 deficiency (think stepwise)?
So there is decreased LARS expression and acitivity, which results in a decreased tRNA aminoacylation. This results in stress, namely a high translational demand, with a low amino acid supply.
A high translational demand with a low amino acid supply can result in:
- decreased translation speed
- translation termination at LEE-codons
- misacylation → mistranslation → protein degradation
A new treatment for ARS1 deficiency was developed, a targeted amino acid supplementation treatment. The activity and leucine rescue was researched in fibroblasts.
What was found before and after administration of the treatment (i.e. leucine supplementation)?
- A reduced residual acitivy in aminoacylation, which decreases with higher temperature, was found in LARS deficient fibroblasts
- Leucine supplementation resulted in rescue of function and survival.
What are challenges that are ahead in regard to (rare metabolic) diseases such as a LARS1 deficiency?
- ARS1 deficiences are rare
- Hetereogeneous phenotypes
- Natural history limited → is the disease progressive?
- Low evidence levels
- Minimal access quality amino-acids (for supplementation)
- Optimal dosage unknown
- Lack of approval and reimbursement
N-of-1 trial designs can be very important in researching rare diseases and in developing tailored treatment for these diseases. However, an n-of-1 trial on its own is not neccesarily high of statistical power. What can be done to yield an evidence level of 1 with a n-of-1 trial?
Using multiple n-of-1 trials and performing a meta-analysis on these multiple n-of-1 trials.
UMD (United for Metabolic Diseases) is an national n-of-1-for all platform in the Netherlands. Their mission is to accelerate evidence, approval and access for inherited metabolic diseases. What tools do they have to achieve this?
- Expert board
- Toolbox and templates
- Alternative trial designs
- Personalized outcome measures
- Methodology and statistics
- Policymakers involvement
Drug discovery and development:
What are challenges?
- Duration of drug discovery and development usually takes longer than 10 years.
- Expensive
- High risk and low success rate
What are the advantages of drug repurposing compared to drug discovery and development?
- Duration of drug repurposing usually takes less than 5 years (instead of longer than 10 years).
- More affordable
- Known drug safety
- Reduced pharmacokinetic uncertainty
(However, still not easy)
Why is the use of CRISPR-Cas9 seen as a breakthrough?
- Gene editing without viral insertions, only patient’s own cells.
- More personalized → safer?
What is RNA therapy?
RNA therapy is designed to correct mistakes or mutations in the RNA of someone with a genetic disease. By correcting the mistake, the RNA can then be used to create the protein that the cell needs, taking away the underlying cause of the disease. E.g. anti-sense oligonucleotides for splice site mutations.
How can RNA therapy with oligonucleotides for a certain disease be personalized?
By identifying the mutation and the splice defect of the disease → constructing antisense oligonucleotides (ASOs) that target the splice defect → change in pre-mRNA splicing and protein expression which usually causes cleavage of the mRNA by enzymes (you can also construct ASOs that stabilize mRNA that is normally degraded)
What is another treatment that can be used to treat pyridoxine-dependent epilepsy?
Targeting the AASS enzyme to reduce the accumulation of neurotoxins via drug repurposing and RNA therapy. AASS is an enzyme which lies upstream of the defective gene in the human lysine metabolic pathway.
How can the targeting of the AASS enzyme for the treatment of pyridoxine-dependent epilepsy be researched for its effectiveness?
- In human model systems (e.g. iPSCs)
- In animal model systems (e.g. PDE zebrafish or mice)
