I have a question. I've been pouring over Alector, off and on, for a few weeks. And I still have a very basic question, perhaps the most basic question, which keeps me from pulling the trigger (for anything other than my current small position).
The literature is full of statements that progranulin does not cross the brain blood barrier. And, if one looks at Denali, they've designed a brain penetrant progranulin biologic, PTV:PGRN.
https://www.cell.com/cell/fulltext/S0092-8674(21)00944-2
OTOH, Alector has a monoclonal (anti-sort-1, AL001) that inhibits a PGRN degradation pathway (sort-1) and which is administered to the periphery. Then they wave their magic hands, and point to inhibition of PGRN degradation in the brain.
It's easy to understand why levels of PGRN are increased in the periphery. But how does inhibition of sort-1 in the periphery lead to increased half life of PGRN in the brain? Limited human data to date says that it works, and GSK just paid $700m upfront for AL001 and a sister molecule. So...... there must be a simple answer. But I never hear/see Alector actually addressing this question/issue.
Thanks for any help. Bugging me, and I've spent hours trying to find the answer. BJ?
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