--- Log opened Fri Mar 16 00:00:20 2018
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07:39 < kanzure> "The ideal gene delivery vector: chromallocytes, cell repair nanorobots for chromosome replacement therapy" https://jetpress.org/v16/freitas.pdf
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08:03 < kanzure> https://turingchurch.net/cryonics-for-uploaders-meeting-in-second-life-sunday-march-25-71f3f9310b27
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09:10 < kanzure> to limit adult viral gene therapy response, why not temporary immunosuppressants + bubble boy lifestyle + whole blood filtering/replacement (or at least wait for everything to probably be recycled). would that be enough or are immunosuppressants not strong enough?
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09:26 < nmz787_> hmm
09:26 < nmz787_> not a bad question
09:28 < kanzure> the procedure would be: 3-4 weeks on immunosupressants in bubble boy lifestlye, stay on immunosupressants and receive dose of viral gene therapy, continue to stay on immunosuppressants for another 5 weeks until capsids are degraded or filtered out completely.
09:28 < nmz787_> asked my doc friend
09:28 < kanzure> and you could also do some monitoring of integration status (if there was any indicator encoded into the delivered dna) and you could keep dosing until you're relatively happy with total efficiency or total transfection rate
09:29 < kanzure> most people would probably not like having to take such a huge chunk out of their life for 12 weeks or whatever, but i'm sure there will be some people that want (or need) the gene therapy more than they care about 12 weeks of a weird lifestyle
09:31 < nmz787_> 12 weeks isn't really that long for a mega-transformation
09:32 < kanzure> "Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732124/
09:32 < kanzure> "A cellular immune response against the AAV capsid can clearly be triggered by the administration of recombinant AAVs, but it has also to be pointed out that a transient immunosuppression might be sufficient to circumvent potential problems posed by such a response (Nathwani et al., 2011). On the other hand, immunosuppression has its own set of drawbacks, such as an increased risk for ...
09:32 < kanzure> ...infection, and the precise immunosuppression regimen used can be critical. Thus, it has been reported that, depending on the protocol used, immunosuppression can give rise to antibodies against the transgene, presumably as a result of a depletion of CD4+CD25+FoxP3+ regulatory T cells (Tregs) (Mingozzi et al., 2007). Taken together, these and other results obtained with immunosupression in AAV ...
09:32 < kanzure> ...gene therapy suggest that while immunosuppression will likely be an important tool, it is unlikely to be a panacea against capsid-specific cellular immune responses."
09:33 < kanzure> ok well if immunosuppression is insufficient then you could just add chemotherapy (i'm kidding)
09:35 < kanzure> "Theoretically, it might be possible to identify AAV serotypes/variants for which a specific patient is seronegative. However, even if it were possible to identify for each individual an AAV serotype/variant with the desired tropism and for which the particular individual is seronegative, it is highly unlikely that such an individualized approach is practical."
09:35 < kanzure> hmm.
09:35 < kanzure> "Over the past years, significant effort has been put into the development of “designer” AAV variants that show increased resistance to NAbs. Some of these approaches are based on the targeted alteration of known antigenic regions of a particular serotype (Lochrie et al., 2006), others are based on the selection of AAV variants with increased resistance to NAbs from a large library of AAV ...
09:36 < kanzure> ...variants (Maheshri et al., 2006) or a combination of both approaches (Maersch et al., 2010) in a process called directed evolution (Fig. 1D)."
09:36 < kanzure> womp womp "While directed evolution and other methods of capsid engineering have been quite successful in isolating AAV variants with improved neutralization profiles (Bartel et al., 2011), none of the variants identified are completely resistant to NAbs and, as mutations accumulate, both the infectivity of the mutants as well as their tissue tropism can be affected."
09:37 < kanzure> "Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392987/
09:38 < kanzure> "A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222518/
09:39 < kanzure> "A recent publication (Monteilhet et al., 2011) supports the possible utility of plasmapheresis to deplete NAbs prior to vector administration. In their study, Masurier and colleagues analyzed the presence of neutralizing factors against AAV1, 2, 6, and 8 in 10 patients who were undergoing repeated plasmapheresis for a variety of clinical indications (Monteilhet et al., 2011). Importantly, ...
09:39 < kanzure> ...they were able to demonstrate that frequent plasmapheresis could lead to a substantial reduction in neutralizing factors. In several patients who had low neutralizing titers (≤1/20) before initiation of the plasmapheresis protocol, they were able to deplete neutralizing factors to undetectable levels after several rounds of plasmapheresis (Monteilhet et al., 2011). Similarly, Hurlbut and ...
09:39 < kanzure> ...colleagues demonstrated that a single round of plasmapheresis can result in an almost three-fold drop in neutralizing antibody titers (Hurlbut et al., 2010). These authors conclude that, if combined with high vector doses, plasmapheresis would allow the treatment of up to 90% of potential patients with AAV8-based vectors (Hurlbut et al., 2010)—although this might be an overly optimistic ...
09:40 < kanzure> ...estimate."
09:40 < kanzure> okay so immunosuppressants + plasmapheresis around the clock for the whole treatment period.
09:40 < kanzure> "Flushing out antibodies to make AAV gene therapy available to more patients" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596520/
09:42 < kanzure> um..
09:43 < kanzure> "Overcoming preexisting humoral immunity to AAV using capsid decoys" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095828/
09:43 < kanzure> "We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but ...
09:43 < kanzure> ...cannot enter a target cell."
09:43 < kanzure> but you still have an active ongoing immune response...?
09:44 < kanzure> "When mice were immunized with high doses of IVIg, resulting in very high NAb titers (>1:3000), we were not able to rescue liver transduction even by adding a 1000X excess of empty capsids (Fig. 2D). Although anti-AAV8 NAb titers higher than 1:1000 are rarely found in humans naïve to AAV vectors (table S1), they are common in subjects dosed with AAV vectors, suggesting that formulation of ...
09:45 < kanzure> ...vector in empty capsids may need to be coupled with other strategies [such as plasmapheresis (17) or pharmacological methods (16)] to allow for vector readministration."
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09:56 < kanzure> "Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104587/
09:56 < kanzure> "Here we demonstrate that in mice, AAV vectors associated with extracellular vesicles (EVs) can evade human anti-AAV neutralizing antibodies."
10:13 < kanzure> ".... show that the AAV DNA genome and capsid structure is being sensed by Toll-like receptor (TLR) 9 and TLR2, respectively, therefore working as adjuvants for the elicitation of immune responses"
10:13 < kanzure> from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758940/ (good overview of immunogenicity concerns)
10:18 < kanzure> directed evolution of capsids against patient-specific neutralizing antibodies https://www.sciencedirect.com/science/article/pii/S1525001616303070
10:19 < kanzure> and here too http://www.pnas.org/content/114/24/E4812.short
10:23 < kanzure> rapamycin + prednisolone for immunosuppression for AAV9 antibody depletion https://www.sciencedirect.com/science/article/pii/S2329050117300074
10:27 < kanzure> biohack the planet 2018 talk submission https://docs.google.com/forms/d/e/1FAIpQLSergf_JgOGvVAdzz-T5yuhZSYP9kFjgoQ2VjUlL208FcXNaeQ/viewform
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10:28 < kanzure> https://www.xconomy.com/san-francisco/2018/03/13/no-self-editing-biohacker-josiah-zayner-cant-stop-living-out-loud/
10:43 < mrdata> but is he healthy?
10:43 < mrdata> or is this madness an illness
10:52 < nmz787_> haha, that one author's name is 'hurlbut'
10:53  * nmz787_ is the new buttbot
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11:37 < razzy> yoleaux: do ywant to modify yr head?
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12:47 < kanzure> "Widespread transcriptional scanning in testes modulates gene evolution rates" https://www.biorxiv.org/content/early/2018/03/14/282129
12:55 < kanzure> "electrospun nanotubes are meters long" is this true?
13:03 < fenn> at least centimeters, and you can twist them into continuous yarns
13:03 < fenn> longest so far is 550mm
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13:19 < kanzure> oxidation damage to store data on those tho?
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17:16 < kanzure> hmph
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17:42 < juul> http://philome.la/johnayliff/seedship/play
17:57 < nmz787_> superkuh: any hardware you know of that might be useful for beamforming experiments, something with several to many channels that can be adjusted in frequency but also freq/phase modulated?
17:57 < nmz787_> superkuh: idea is related to dielectrophoresis
17:59 < nmz787_> superkuh: looks like maybe 0-10MHz is a reasonable range to start
18:00 < nmz787_> or rather 0.01 MHz - 10 MHz
18:00 < nmz787_> idk, maybe DC would be interesting to be able to do too
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18:52 < kanzure> +w5n 5
18:52 < kanzure> +w5n 5
18:52 < kanzure> +we1r5q1r/93131r/asf1da
18:52 < kanzure> fffff
18:52 < kanzure> +w5n 5
18:53 < kanzure> s60eth5ng 5s wr6ng
18:58 < nmz787_> http://synchro-microfluidics.com/
18:58 < nmz787_> "Aspect ratios 30:1 and potentially higher; Very smooth walls with low roughness, wall angles can be adjusted to meet product requirements; Small structures down to 230 nm; Depth/ heights from 10nm to 400um"
19:01 < nmz787_> maybe made by this http://www.sunmediaventures.in/Appendix%20A%20-%20SQM%20System%20Specification,%20%20Revision%20H.pdf
19:04 < nmz787_> SQM Technical Description: Stack Module (STM) – (Optional); Cleaner/Developer Module (CDM); Substrate Coating Module (SCM); Resist Curing Module (RCM); Laser Beam Recorder (LBR); Sputtering Module (SPM); Handling System; Man Machine Interface (MMI); Control System
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22:02 < superkuh> nmz787_, rotman lens?
22:02 < superkuh> Not exactly low frequency (0.1-10 MHz) usually but it's what comes to mind.
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--- Log closed Sat Mar 17 00:00:21 2018