Indications: Huntington’s Disease, Alzheimer’s Disease Physician Information Specialty: Neurology Location: London, United Kingdom
Published: March 16, 2015
Number of pages:12
ISIS-SMNRx data for Spinal Muscular Atrophy shows brain penetration by an ASO and is a positive for the development of ASO HD-SNP for Huntington’s Disease (ISIS).
An AAV-1 construct presentation from Lisa Stanek showed amazing data where their group got widespread transfection of their virus upon stereotactic injection into the striatum with retrograde transport to the cortex (SNY).
The AMARRYLIS trial of PF-02545920 targeting PDE10 is underway, and Omeros toxicity may be a positive for Pfizer if its compound-related and not mechanism-related (PFE).
There has been some nice selectivity data for the ZFP TF – Huntingtin Repressor. Sangamo has selected a lead compound, they’ve done a toxicity study in a relevant model (SGMO, SHPG).
There are still questions regarding the mechanism of PBT2 in Huntington’s Disease (PRAN).
Would this CSF technique be useful in other trials?
Yes, basically any trial in which the aim is lowering to lower mutant huntingtin, and there are a number of small molecule approaches as well as the antisense oligonucleotide approaches. Various different teams are working on different approaches. There was a very interesting talk by Lisa Stanek from Genzyme. They are one of the people who used RNA interference type, you know, silencing RNA rather than the ASO drugs. The Genzyme approach is virally delivered using
Yes, basically any trial in which the aim is lowering to lower mutant huntingtin, and there are a number of small molecule approaches as well as the antisense oligonucleotide approaches. Various different teams are working on different approaches. There was a very interesting talk by Lisa Stanek from Genzyme. They are one of the people who used RNA interference type, you know, silencing RNA rather than the ASO drugs. The Genzyme approach is virally delivered using adeno-associated virus (AAV). Then using AAV-1, and it is not clear what they’ve done to it. But, they showed some absolutely amazing data that was essentially gamechanging, there a lot of debate on whether it is important to drug the cortex or the striatum of whether its necessary to drug both in order to achieve meaningful clinical improvement. And we just won’t know until we try it in humans. Genzyme has carried out stereotactic injections into the striatum of wild-type rhesus monkeys using that AAV-1 virus, and the penetration that they showed indicates that once you inject the striatum in these monkeys, you get very widespread transfection, in this case, of the cortex. So, it looks like in drugging the striatum, you get retrograde transport up into the corticostraital neurons and up into the frontal and prefrontal cortex.
This has never been seen before and this is huge because its kindo of the holy grail in terms of delivering gene-silencing drugs. The idea that you could inject into the most severely affected area, the striatum, and then see secondary penetration of the AAV-1 and of course thereby the drug into the cortex. If that happens in humans, and it is a big if, then that would be really impressive stuff. So, that AAV-1 construct is owned by Genzyme, and they are going to use it for their own drug. They’re partnered with the CHDI foundation, who organized the conference and who are a non-profit drug foundation.
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