Great breakdown of the biology. I specifically enjoyed learning about the distinction between peripheral and brain apoE. On a whole I think you did a great job showing me pluses and minuses. One thing I keep taking away from these targeted interventions is that there are pluses and minus for all things and that we're going to all die from something. At this point in my life I would not take something to alter a gene expression in hopes of avoiding one type of death and possibly increasing another
Thank you for this review. What is your view of the further pipeline of Lexeo and possibly voyager therapeutics of using e4 silence/ e4 ( Christchurch) transfection in homozygotes? The voyager capsid iv one time delivery is said to be not liver toxic and to be brain focussed in delivery. Also perhaps ribozyme / rna level re gene engineering to transform e4 to e3 , say in homozygotes first , are another option as per ezenomics (Korean company Roche licensed/ agreement?
There is an important general parallel with huntingdons similar gene research eg the history up till the latest uniqure . In HD the patient community was *globally* enrolled in clear biological tracking programs allowing researchers access to data. The community was trusted to choose themselves to be brave and drive therapy way faster than traditionally thought possible as they better than anyone knew the fate that awaited them. People with HD are actively involved. As a result therapies now launching like uniqure and Skyhawk therapeutics oral splice modulator is now looking very good. Will these change outcomes? Not yet clear but looking hopeful.
If a gene therapy for example changes the trajectory instead of thinking how will a 70 year old cope with this maybe we should think about the future where it rolls out in 50 year olds, because we learnt from brave consenting 70 year olds? Getting therapies that change the outcomes for pre- symptomatic people - so they never have to face what the current generations do - that seems so important. I do wonder if the medical and research community can go a lot faster in the most at risk group e4/4 in similar ways. The average time to any new drugs of ~15 years(?) is I feel unacceptable and the top down model has to change. That to me is the most ethical approach , responding to your comment. Of course early treatments are expensive and inequitable, but do get much cheaper and accessible. We can be potentially immobilised by thinking of every possible complexity or get on with trying intelligently and thoughtfully in collaboration with the communities involved to speed progress up. HD is a good example. Manhattan project is another.
Strategic focussed fast moving start-up culture today is yet another however imperfect.
Great breakdown of the biology. I specifically enjoyed learning about the distinction between peripheral and brain apoE. On a whole I think you did a great job showing me pluses and minuses. One thing I keep taking away from these targeted interventions is that there are pluses and minus for all things and that we're going to all die from something. At this point in my life I would not take something to alter a gene expression in hopes of avoiding one type of death and possibly increasing another
Thank you for this review. What is your view of the further pipeline of Lexeo and possibly voyager therapeutics of using e4 silence/ e4 ( Christchurch) transfection in homozygotes? The voyager capsid iv one time delivery is said to be not liver toxic and to be brain focussed in delivery. Also perhaps ribozyme / rna level re gene engineering to transform e4 to e3 , say in homozygotes first , are another option as per ezenomics (Korean company Roche licensed/ agreement?
There is an important general parallel with huntingdons similar gene research eg the history up till the latest uniqure . In HD the patient community was *globally* enrolled in clear biological tracking programs allowing researchers access to data. The community was trusted to choose themselves to be brave and drive therapy way faster than traditionally thought possible as they better than anyone knew the fate that awaited them. People with HD are actively involved. As a result therapies now launching like uniqure and Skyhawk therapeutics oral splice modulator is now looking very good. Will these change outcomes? Not yet clear but looking hopeful.
If a gene therapy for example changes the trajectory instead of thinking how will a 70 year old cope with this maybe we should think about the future where it rolls out in 50 year olds, because we learnt from brave consenting 70 year olds? Getting therapies that change the outcomes for pre- symptomatic people - so they never have to face what the current generations do - that seems so important. I do wonder if the medical and research community can go a lot faster in the most at risk group e4/4 in similar ways. The average time to any new drugs of ~15 years(?) is I feel unacceptable and the top down model has to change. That to me is the most ethical approach , responding to your comment. Of course early treatments are expensive and inequitable, but do get much cheaper and accessible. We can be potentially immobilised by thinking of every possible complexity or get on with trying intelligently and thoughtfully in collaboration with the communities involved to speed progress up. HD is a good example. Manhattan project is another.
Strategic focussed fast moving start-up culture today is yet another however imperfect.
So clearly elucidated. Thank you!
Interesting article. On my mom’s side of the family, dementia is common.
Thank you for this outstanding summary!