Det er bare en person som har trykket på lenken til den prekliniske infarkt-studien, så jeg trekker ut noen vesentlige poenger:
Litt mer detaljert om hva man har fått til preklinisk, og forsøker å få til klinisk:
“The mainstays of post-MI [infarkt] therapy are revascularization in the acute setting and neurohormonal blockade combined with blood pressure control in the acute and sub-acute window (Table S3). Our findings suggest that purified VEGF mRNA has the unique ability to combine the targets of these treatment modalities, i.e., increased blood supply, decreased cardiac fibrosis, and increased cardiac function, in a neurohormonal-independent manner that can be administered during the sub-acute time window after an MI.”
Og så et lengre avsnitt som diskuterer utfordringene med skjørheten til “naked” mRNA og opptak av mRNA i cellene, og problemene med lipid-baserte leveringsløsninger, som løser noe, men skaper nye problemer. Det de gjør er å injisere mRNA i saltvann rett i hjertemuskulaturen for å unngå RNases i blodomløpet, som er enzymer som spiser opp RNA. De får altså disse resultatene basert på hva som “spontant” blir tatt opp i cellene. Og det er fryktelig mye mindre enn noe som blir levert innkapslet - eller med PCI.
Dette er altså skrevet av Astra Zenecas egne forskere, og det er her opplagt at en effektiv non-toxic “naked delivery” av deres mRNA er hva de trenger for enda bedre resultater:
“Interestingly, while RNA is rapidly degraded in the bloodstream within minutes, when directly injected into the myocardium, we saw prolonged VEGF protein levels. Indeed, with VEGF mRNA cardiac injections, at both 10 and 100 μg at 6 and 24 hr (in mouse and rat), the systemic exposure of human VEGF-A protein never was above the lower limit of quantification for the assay (data not shown), likely from RNase exposure. The cause of this prolonged duration of protein, we hypothesize, is based on a combination of factors. First, when directly injected into the heart, the mRNA will remain tissue specific and initially is seen in both intra-cardiomyocytes, but also organized along the cardiac sarcolemma, potentially acting as a protected reservoir of VEGF mRNA (Figure 3M). Second and in line with previous findings, we observed the uptake of the mRNA to be a saturable process with the production of the VEGF-A protein to be almost linear over a wide range of mRNA doses.7, 11 To the best of our knowledge, a clear explanation for such saturation is still lacking. Although the cellular mRNA uptake per se has been suggested to be nucleic acid specific, receptor mediated, and ion and energy dependent, other mechanisms including translation and secretion may contribute to the apparent saturation in protein production observed.39, 57 Third, when compared to VEGF protein production in previous studies,7, 11 a non-lipid-based carrier may also prolong VEGF mRNA protein expression, potentially because of avoidance of the local pro-inflammatory effects of lipid carriers and the interaction between a lipid-based delivery system and IFN-1 leading to more rapid mRNA clearance.21 In addition, lipid carriers also may cause local cell necrosis, autophagy, local inflammation, and oxidative damage, and activate local apoptotic pathways.58 This combination of interstitial localization acting as a protective reservoir, away from RNases found in the bloodstream, a saturable, active uptake mechanism, acting as a control on mRNA cellular uptake, and the use of a non-toxic carrier may allow for the prolonged expression and the consequential functional improvements in a large-animal MI model.”
Bare så det ikke blir noen misforståelser - det er evt. studiet under jeg tror Astra Zeneca fint har rukket å replikere med PCI løpet av seks uker: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269526/pdf/41598_2018_Article_35570.pdf
Enkel intradermal (i huden) injeksjon av AZD8601 og Amphinex i mus, og enkel belysning. maks. 28 dager datainnsamling.