3 ms·

Does anyone have a link to a more technical description of this therapy? From what I've found it's a small anti-sense RNA targeting the mutant huntingtin gene.

Does anyone have a link to a more technical description of this therapy? From what I've found it's a small anti-sense RNA targeting the mutant huntingtin gene. But I don't see a description of a delivery vehicle, or if there even is one. The drug seems to have pretty big implications if it works, but I'll be frankly amazed if all they had to do was inject the bare nucleic acid into the CSF.

dghughes 9y ago
This PDF from 2016 looks like it's discussing the trial for the drug http://huntingtonstudygroup.org/wp-content/uploads/2016/05/HD-Insights-Vol.-13-CORRECTED_Retraction_FINALMay4.pdf http://huntingtonstudygroup.org/wp-content/uploads/2016/05/H...
- Brakenshire 9y ago
  I followed those links through, and found this article discussing the effect of injecting anti-sense oligonucleotides into mice: http://www.cell.com/neuron/pdf/S0896-6273(12)00444-8.pdf http://www.cell.com/neuron/pdf/S0896-6273(12)00444-8.pdf > To determine the distribution and cellular uptake of antisense oligonucleotides (ASOs) delivered by infusion into the CNS, an antibody that selectively recognizes the phosphorthioate backbone of the ASOs (see Figure S2 A for additional saline controls from the various brain regions) was used to probe coronal sections from the olfactory bulb to the cerebellum (see Figure S2B for schematic of sectioning and dissections). Following a two week infusion of the HuASO into nontransgenic animals, ASO accumulation was detected in the neurons of most brain regions, including the frontal cortex, striatum, thalamus, midbrain, brainstem, and cerebellum, with the exception of dense regions of white matter and cerebellar granule cells (Figure 2 A). ASOs were also present in neuronal nuclei, cell bodies and neurites, as determined by colocalization of accumulated ASOs with the neuronal marker NeuN (Figure 2B). ASOs also accumulated in nonneuronal cells, including glial fibrillary acidic protein (GFAP)-expressing astrocytes (Figure 2B)
  - ghkbrew 9y ago
    Impressive. An important point here seems to be that these ASO's have a chemically modified backbone which prevents degradation by exonucleases. But the bases are un-modified allowing complimentary pairing and activation of RNAse H activity. Even so, I'm surprised they're able to cross the cell membrane in high enough quantities to have therapeutic effects. Apparently, these techniques have been around since the mid-nineties or so. TIL...
ejstronge 9y ago
Here's a link to what I presume is the trial on ClinicalTrials.gov[1]. Notably, the maker, Ionis, is trying this approach on dozens of diseases[2]. I couldn't see a reference about a potential vehicle for the antisense oligonucleotide... [1] https://clinicaltrials.gov/ct2/show/NCT02519036?term=ionis&cond=Huntington+Disease&rank=1 https://clinicaltrials.gov/ct2/show/NCT02519036?term=ionis&c... [2] https://clinicaltrials.gov/ct2/results?cond=&term=ionis&cntry1=&state1=&Search=Search https://clinicaltrials.gov/ct2/results?cond=&term=ionis&cntr...

dghughes 9y ago

This PDF from 2016 looks like it's discussing the trial for the drug http://huntingtonstudygroup.org/wp-content/uploads/2016/05/HD-Insights-Vol.-13-CORRECTED_Retraction_FINALMay4.pdf http://huntingtonstudygroup.org/wp-content/uploads/2016/05/H...

Brakenshire 9y ago
I followed those links through, and found this article discussing the effect of injecting anti-sense oligonucleotides into mice: http://www.cell.com/neuron/pdf/S0896-6273(12)00444-8.pdf http://www.cell.com/neuron/pdf/S0896-6273(12)00444-8.pdf > To determine the distribution and cellular uptake of antisense oligonucleotides (ASOs) delivered by infusion into the CNS, an antibody that selectively recognizes the phosphorthioate backbone of the ASOs (see Figure S2 A for additional saline controls from the various brain regions) was used to probe coronal sections from the olfactory bulb to the cerebellum (see Figure S2B for schematic of sectioning and dissections). Following a two week infusion of the HuASO into nontransgenic animals, ASO accumulation was detected in the neurons of most brain regions, including the frontal cortex, striatum, thalamus, midbrain, brainstem, and cerebellum, with the exception of dense regions of white matter and cerebellar granule cells (Figure 2 A). ASOs were also present in neuronal nuclei, cell bodies and neurites, as determined by colocalization of accumulated ASOs with the neuronal marker NeuN (Figure 2B). ASOs also accumulated in nonneuronal cells, including glial fibrillary acidic protein (GFAP)-expressing astrocytes (Figure 2B)
- ghkbrew 9y ago
  Impressive. An important point here seems to be that these ASO's have a chemically modified backbone which prevents degradation by exonucleases. But the bases are un-modified allowing complimentary pairing and activation of RNAse H activity. Even so, I'm surprised they're able to cross the cell membrane in high enough quantities to have therapeutic effects. Apparently, these techniques have been around since the mid-nineties or so. TIL...

ejstronge 9y ago

Here's a link to what I presume is the trial on ClinicalTrials.gov[1]. Notably, the maker, Ionis, is trying this approach on dozens of diseases[2]. I couldn't see a reference about a potential vehicle for the antisense oligonucleotide... [1] https://clinicaltrials.gov/ct2/show/NCT02519036?term=ionis&cond=Huntington+Disease&rank=1 https://clinicaltrials.gov/ct2/show/NCT02519036?term=ionis&c... [2] https://clinicaltrials.gov/ct2/results?cond=&term=ionis&cntry1=&state1=&Search=Search https://clinicaltrials.gov/ct2/results?cond=&term=ionis&cntr...