| Setting | Model | Evidence (PMX / C5aR1 inhibitor study) | |||||
|---|---|---|---|---|---|---|---|
| MPTP | 2020114 pdf p12 mRNA | ||||||
| Mitopark | 2020118 pdf p12 mRNA | ||||||
| In vitro | |||||||
| In vivo / 6OHDA | MCC | aSyn pdf, p3, ohga PFF → 1 DA | (pre & post) PMX205-9-10n-9 1 DA / TSPO signal (18F-DPA-714) C5aR deletion-9 1 DA | LPS-primed post, PMX205-9-10nM stimulated, WT mouse, 1 LPS DA, 1 LPS post, ↑ IL-1b (preventive) PMX205-9 1 DA, 1 IL-1b PMX205-9 1 DA, ↑ TNFa, IL-1b PMX205-9 1 DA (supernant, releaser) | C5aR deletion → control PMX205-9 1 DA | 1 IL-1b PMX205-9 1 DA, 1 IL-1b PMX205-9 1 DA, 1 TNFa, IL-1b ASC, microglia 1 amphetamine response (Vasiliou, 2018) | |
| 6OHDA mouse | IL-1b caspase-1, ASC, IL-1b PMX205, IL-1b ASC inflammation, Pro-caspase-1 1 DA, 1 pro-IL-1b, 1 active caspase-1, 1 IL-1b. C5aR1-mediated, 1 IL-1b (supernant, releaser) | ||||||
| In vitro | human monocyte-derived microglia-like (MDMi) | ||||||
Woodruff’s study plan with C5aR1 inhibitors
| title | objective | [prophylactic / therapeutic] design (PMX205, tool drug) | [다른 처리 (PMX205, tool drug)] | [분석방법] | budget | |
|---|---|---|---|---|---|---|
| Study 1 February 25, 2019 - March 31, 2020 COCKPI-T study | (A) In vivo 6-OHDA preclinical mouse model: |
determine the therapeutic effectiveness of a new-generation C5aR1 inhibitor (PMX301) in the 6-OHDA mouse model, IC50 과 비교? PMX301 IC50=64Nm 근데 slide9 에서는 pk 단위가 ng/ml 인데 분자량 몰라서 비교 못 하겠네. 아니 slide10 에 PMX301 IC50=5.71uM, MW=1518 Da |
[prophylactic 처리 (PMX205, tool drug)] 6OHDA 4 주 CULL, Aneural counting 말하겠네. [therapeutic 처리 (PMX205, tool drug)] neuronal counting 말하겠네. MCC950 을 동시시작으로 반정도? | (preventive PMX205-9 1 DA), 1 IL-1b, 1 TNF-a, IL-6 | (preventive PMX205-9 1 DA), 1 IL-1b, 1 TNF-a, IL-6 | AUD $100,000 |
| (B) In vitro human monocyte-derived microglia-like (MDMi) study. | validate the C5aR1 target in a human microglia model of α-syn-mediated inflammation |
LPS 군은 PD를 나타내기 위해 사용. NLRP3 level 안 되나? (slide24에 data있네) C5aR1 level 억제만 하지 양 줄이는 거 아니므로 볼 수 없겠지 | [PMX205 → ↑ IL-1b, ↑ ASC, ↑NLRP3 (preventive) PMX205-9 1 DA, 1 IL-1b, 1 TNF-a (supernant, releaser)] | |||
| Study 2 April 1, 2020 - March 31, 2021 | (A) In vivo PFF-Syn preclinical mouse model | determine the therapeutic effectiveness of a new-generation C5aR1 inhibitor (PMX301) in aSyn PFF mice |
Mouse aSyn PFF (accelerated PD model)임. 아마 이 시... Post-onset (PMX301) dosed 1 month after PFF-Syn injection. PFF 주입 4 month 분석 예정 (Q4 2020 분석 예정) | (pre & post) PMX205-9-10n-9 1 DA, TSPO (18F-DPA-714) | Ongoing 처리 후에는 결과만 안나오면 됨 (load/spreading 이후) 2021/09/24 DA, (aSyn 9, 결과 1 PFF, aSyn (load/spreading)) → 데... PMX301 1 PFF | AUD $200,000 |
| (B) In vivo 6-OHDA preclinical mouse model: | compare the efficacy of PMX301 to two newer analogues (PMX302 and PMX318,) | |||||
| In vivo / Blood neurotriphi? | PMX301 → ↑ C5aR inhibition, LPS-mediated BBB disruption (Bui 9) | |||||
Screening
DD
Pharmacodynamics chart (CHO-C5aR1 pERK dose-response curves for PMX205 / PMX301, n=3; sub-panel Time profile -PMX301 v.s. PMX205, n=4 % blood neutrophils bar charts at 1 min / 30 min / 4 hours after C5a injection - kept as evidence in body_r03_c01.jpg / body_r04_c01.jpg. Caption: PMX301 blocks C5aR activation in vivo 24hrs, and is more effective than PMX205; sub-caption: C5a-induced neutrophilia assay.)
| Content | ||
|---|---|---|
| usuality | Correction data 로 되겠지? | |
| human data postmortem |
Increase in PD? Severity correlation? → Postmortem brain, | |
| At least CSF to confirm repeat (since this is not large scale, publication, but just UC's internal data?) (inline CSF Healthy/PD bar chart in `body_r04_c01.jpg`) | ||
| target population? | If clear differentiation from postmortem data, then we don't need patient stratification | |
| differentiation from NLRP3 i | Can we choose between two (based on effect size, correlation, or different pathway? We don't want two neuroinflammation [drugs same MOA] | |
| efficacy | 6ohda alone? Who will do this, Tcal? Prophylactic only? | |
| GBA-PD |
Rationale: ↑ C5a & C5aR in GD (C5a-C5aR axis is over-activated in GBA-PD): Tareni allele with Asp499Val and KO mice and GC patients C5ar1 -/- rescued survival of CBE(GBA inhibitor) treated mice and GCs accumulation and inflammation. (Pandey, 2017 #1668) MOA: ↑ GlcCer → ↑ C5a & C5aR Plan: why not test C5aR inhibitor in GBA-PD animal model? (conditional/ C5aR gene deletion in the model?) | |
| marker |
| |
| microglial imaging |
TSPO 등 correlate with C5a? microglia activation? Effect on aSyn spreading? | |
e: i) TV (at least this should be included in DD?) ii) TE BM (at least this asseet 으로 간주한다면 이것들을 licensing 후에 하던가? 누가 TV/BM stuff?
| Genetic link? | Human tissue | |
|---|---|---|
| ? |
(microglia stain thumbnail with caption `brains - and localised to microglia` and `no reproduction permission` annotation) 2018 Gordon abstract) C5aR1 expression on (activated) microglia (quantitative data not shown) | |
|
• CSF: (inline CSF C5a (ng/ml) bar chart, Healthy ~0.4 vs PD ~1.0 ng/ml, kept as evidence in `body_r05_c01.jpg`) We obtained these from a collaborator in the USA who had a collection of post-mortem samples from a whole bank. All we were given were PD vs HC, and no other clinical information. Is there any data that CNS-C5a- or C5aR1- level is correlated with PD disease severity/progression rate? (20210930 Nidhi: I don't think we asked about disease progressions and C5aR1/C5a levels and # of patients questions.) | ||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
top in vivo / in vitro table / column placement | the wide multi-column table for MPTP / Mitopark / In vitro / In vivo / 6OHDA mouse rows has 6+ columns of evidence cells; per-row column placement is partly inferred from cell width visible in body_r01_c01.jpg. | low confidence on column-by-row placement. |
Woodruff's study plan / Study 1 (B) MDMi cell | reads LPS 군은 PD를 나타내기 위해 사용. NLRP3 level 안 되나? (slide24에 data있네) C5aR1 level 억제만 하지 양 줄이는 거 아니므로 볼 수 없겠지 (red text); preserved verbatim. | source typography preserved. |
Woodruff's study plan / Study 2 (A) PFF-Syn / 분석방법 cell | reads 2021/09/24 DA, (aSyn 9, 결과 1 PFF, aSyn (load/spreading)) → 데... PMX301 1 PFF; the trailing → 데... token is partly clipped. | clipped; partial. |
DD section / GBA-PD cell / Tareni allele Asp499Val | reads Tareni allele with Asp499Val and KO mice and GC patients (likely a typo for Tareyev or Tarrytown or similar); preserved verbatim. | low confidence on Tareni token. |