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.
Branaplam
Led to potential peripheral neuropathy in some participants. Off-target effects along with target engagement (HTT lowering) BUT ALSO lead to increases in NFL, and most concerningly increases in ventricular volume.
PTC518
PTC518 is safe and shows target engagement at 12 weeks:
No increases in NFL in treated patients, which was observed with both Branaplam and tominersen. So this is looking promising.
RNAi in HD
- RNAi is a physiological pathway to degrade mature mRNA
- miRNA is one of the mechanisms of the RNAi pathway
- they require gene therapy approaches
AMT-130 in HD
AMT-130 decreases mHTT in CSF
* mHTT decreases at low doses.
* adverse events with the higher dose
* immunologic response to AAV
* Ad integrum recovery
* Recruitment restarted in 2023.
* New cohort – immunosuppression to prevent the immunologic response.
pathological changes in HD noted in the:
motor and prefrontal cortex, specifically the basal ganglia, striatum and the cerebellum
