Huntington's Disease Flashcards
CAG repeat penetrances:
< 29 = not pathogenic
29 - 35 = not pathogenic
36 - 39 = pathogenic (varying risk %)
>39 - always causes HD
CAG 39 - 39 penetrance risk %
36 - 25%
37 - 50%
38 - 75%
39 - 90%
Pattern of neurodegeneration in HD
- The first incidence of loss is in the cortico-striatal connections.
- Selective neurodegeneration initially begins first in the MSNs in the striatum.
- This then leads to generalised atrophy.
- Loss of functional and structural connectivity between the cortex and the striatum plays a major role in the disease symptomatology.
Clinical features of HD
- Movement disorder:
o Chorea/dystonia… parkinsonism - Cognitive impairment
o Subcortical cortical impairment… eventually leading to dementia - Neuropsychiatric
o Apathy (progresses linearly), depression, anxiety, OCD-like - Extra CNS (outside of the CNS)
o Weight loss – very prominent.
functions of the WT HTT protein
- Large protein numerous interactions
- Ubiquitously expressed.
- Ciliogenesis, vesicle trafficking, cell division, transcription, autophagy
- Essential role in neurodevelopment.
HTT lowering - non-allele selective
- All the population can be targeted with a single drug
- There is a risk of impairing the function of the WT protein
- However 50% decrease in the levels of wtHTT in the adult human brain are potentially safe.
HTT lowering - allele selective
- SNPs > 3 drugs required to target 80% of the population:
o Each one with an independent CT. - Allele-selective approaches
o Single nucleotide polymorphisms (SNP)
o Expanded CAG (off-target effects)
HTT lowering - delivery strategies - single agent (transient)
- Antisense oligonucleotides (ASOs)
- Small molecules
HTT lowering - delivery strategies (gene therapy - permanent expression)
- MicroRNA (miRNA) – RNA interference (RNAi)
- CRISPR-Cas9
- Zinc-finger proteins (ZFP)
Current ASOs in clinical development for HD
- Tominersen (non-allele selective)
- WVE-003 (allele selective)
- VO659 (allele preferential)
Tominersen
- Allele non-specific ASO.
- Administered through intrathecal injection into the CSF via lumbar puncture.
- know most about the studies - generation HD1 being terminated early due to disproportionate increase in ventricular volume with no clinically significant changes.
Possible causes of early termination of tominersen.
- Dose was too high/too frequent
- Chemical inflammation triggered by the ASO
- Too late in the disease course?
- Exon 1 toxicity?
- Spatial distribution of the drug
- Non-allele selectivity approach
NFL as a biomarker of therapeutic window:
- If you overdose/cause harm in some way, it is likely that NFL will increase.
- If you in the therapeutic window, it is expected that NFL will go down.
- If you underdose, it is likely that NFL (which is increased in HD) will not change.
VO659
targets the CAG repeat
* Basket trail: SCA1, SCA3, HD
* Steric hindrance of protein synthesis
o SCA3 > exon skipping
* Allelic preference for longer CAG
* Good distribution
* Very high risk of off-target effects.
splicing modulation in HD
- Orally administered as can cross the BBB
- Splicing modulation – non allele selective small molecules (Branaplam and PTC518)
Changes the reading frame, leading to premature stop codon, that protein not viable resulting in a decreased production of the HTT protein.
