7 ms·

Safe selective destruction of cells via their internal chemistry, not surface markers, via uptake of lipid-encapsulated programmable suicide gene arrangements.

Safe selective destruction of cells via their internal chemistry, not surface markers, via uptake of lipid-encapsulated programmable suicide gene arrangements. With the right program and a distinctive chemistry to target in the unwanted cell population, this flexible technology has next to no side-effects, and enables rapid development of therapies such as: 1) senescent cell clearance with resorting to chemotherapeutics, something shown to extend life in mice, reduce age-related inflammation, reverse measures of aging in various tissues, and slow the progression of vascular disease. 2) killing cancer cells without chemotherapeutics or immunotherapies. 3) destroying all mature immune cells without chemotherapeutics, an approach that should cure all common forms of autoimmunity (or it would be surprising to find one where it doesn't), and also could be used to reverse a sizable fraction of age-related immune decline, that part of it caused by malfunctioning and incorrectly specialized immune cells. And so forth. It turns out that low-impact selective cell destruction has a great many profoundly important uses in medicine.

petra 10y ago
How does the targeting work , and is it only inside the cell or also outside of it ?
- reasonattlm 10y ago
  From one of the companies working with an implementation: ---------- "Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one that kills p16-expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses." "There's a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn't have any preference for the target cells. It delivers the gene sequence to both healthy and targeted cells. We don't target based on surface markers or other external phenotypic features. We like to say "we kill cells based on what they are thinking, not based on surface markers." So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence - the suicide gene - will be transcribed and drive the cell to apoptosis. However, if p16 isn't active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don't use a virus to deliver our gene sequence, and our liposomal vector isn't immunogenic, our hope is that we should be able to use it multiple times in the same patient."
  - niels_olson 10y ago
    How do you propose to infect cells deep inside solid tumors?How do you target cells that have lost cell surface markers? Your example, p16, is used in many cells intermittently, or only in certain microenvironments . How do you deliver? IV, topical, tumor injection (if so, what about needle tract seeding)?
kelly5 10y ago
For 3) does destroying all mature immune cells also get rid of all immunities that the patient has gained throughout life from vaccines, previous illness, etc? Would it make the patient very fragile, not to have gone through gaining those immunities at a young age?
- reasonattlm 10y ago
  Revaccination, yes, definitely necessary in the idealized case of a complete wipe of immune cells. But that's a small problem in comparison to having a broken immune system. Just get all the vaccinations done following immune repopulation. Part of the problem in old people is that they have too much memory in the immune system, especially of pervasive herpesviruses like cytomegalovirus. Those memory cells take up immunological space that should for preference be occupied by aggressive cells capable of action. Another point: in old people, as a treatment for immunosenescence, immune destruction would probably need to be paired with some form of cell therapy to repopulate the immune system. In young people, not needed, but in the old there is a reduced rate of cell creation - loss of stem cell function, thymic involution, etc. That again, isn't a big challenge at this time, and is something that can already be done. At present sweeping immune destruction is only used for people with fatal autoimmunities like multiple sclerosis because the clearance via chemotherapy isn't something you'd do if you had any better options - it's pretty unpleasant, and produces lasting harm to some degree. Those people who are now five or more years into sustained remission of the disease have functional immunity and are definitely much better off for the procedure, even with its present downsides, given where they were before. If the condition is rhematoid arthritis, however, it becomes much less of an obvious cost-benefit equation, which is why there needs to be a safe, side-effect free method of cell destruction.

petra 10y ago

How does the targeting work , and is it only inside the cell or also outside of it ?

reasonattlm 10y ago
From one of the companies working with an implementation: ---------- "Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one that kills p16-expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses." "There's a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn't have any preference for the target cells. It delivers the gene sequence to both healthy and targeted cells. We don't target based on surface markers or other external phenotypic features. We like to say "we kill cells based on what they are thinking, not based on surface markers." So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence - the suicide gene - will be transcribed and drive the cell to apoptosis. However, if p16 isn't active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don't use a virus to deliver our gene sequence, and our liposomal vector isn't immunogenic, our hope is that we should be able to use it multiple times in the same patient."
- niels_olson 10y ago
  How do you propose to infect cells deep inside solid tumors?How do you target cells that have lost cell surface markers? Your example, p16, is used in many cells intermittently, or only in certain microenvironments . How do you deliver? IV, topical, tumor injection (if so, what about needle tract seeding)?

kelly5 10y ago

For 3) does destroying all mature immune cells also get rid of all immunities that the patient has gained throughout life from vaccines, previous illness, etc? Would it make the patient very fragile, not to have gone through gaining those immunities at a young age?

reasonattlm 10y ago
Revaccination, yes, definitely necessary in the idealized case of a complete wipe of immune cells. But that's a small problem in comparison to having a broken immune system. Just get all the vaccinations done following immune repopulation. Part of the problem in old people is that they have too much memory in the immune system, especially of pervasive herpesviruses like cytomegalovirus. Those memory cells take up immunological space that should for preference be occupied by aggressive cells capable of action. Another point: in old people, as a treatment for immunosenescence, immune destruction would probably need to be paired with some form of cell therapy to repopulate the immune system. In young people, not needed, but in the old there is a reduced rate of cell creation - loss of stem cell function, thymic involution, etc. That again, isn't a big challenge at this time, and is something that can already be done. At present sweeping immune destruction is only used for people with fatal autoimmunities like multiple sclerosis because the clearance via chemotherapy isn't something you'd do if you had any better options - it's pretty unpleasant, and produces lasting harm to some degree. Those people who are now five or more years into sustained remission of the disease have functional immunity and are definitely much better off for the procedure, even with its present downsides, given where they were before. If the condition is rhematoid arthritis, however, it becomes much less of an obvious cost-benefit equation, which is why there needs to be a safe, side-effect free method of cell destruction.