PTV.IDS (DNL310) RESCUES BRAIN BMP LEVELS
Brain BMP — di-22:6-BMP levels (ng/mg protein); groups TfR^-/-^ Vehicle vs. IDS KO; TfR^-/-^ Multi-dose Vehicle / IDS / ETV:IDS; significance markers *** and **.
현재로서 disease에서 BMP가 ↑인지 ↓인지조차 불확실함. Lysosomal dysfnction 의 원인인지, 결과인지도 불명.
PTV:PGRN PRC1 slide: PTV:PGRN restores BMP in brain & CSF in GRN KO mice.
BMP changes in GRN KO mice
(b) Brain — BMP di-44:12 Levels at 24 hrs and 96 hrs; conditions WT Saline / KO Saline / KO 798 / KO 795.
(c) CSF — BMP di-44:12 Levels at 24 hrs and 96 hrs; conditions WT Saline / KO Saline / KO 798 / KO 795.
Didocosahexaenoyl(22:6)-BMP (di-22:6-BMP), a specific species of BMP, is decreased in the urine of LRRK2-knockout mice and in non-human primates treated with chemically distinct LRRK2 kinase inhibitors (PFE-360, MLi-2, and GNE-7915),9
- Sato Shuji (20200620)
- Can GBA Team just use the sam
| BMP | Denali's PGRN | Discovery | ||
| Human data, | Cross sectional Longitudinal | |||
| Assay validation | Preclinical sample | |||
| Clinical sample | CBID? | |||
| Preclinical sample | Pk-pd? | |||
| qualification | Clinical sample |
| LAMP-1 | ||
| PGRN | Serum | |
| For GBA team | Can GBA Team just use the same assay? | Who's responsible? |
| Protein CSF | Who's responsible? DMPK? | |
| M RNA CSF |
Comp Bio
Lysosomal Targets
| scoring | My suggestion |
| Put more weight on lysosomal disorders, lysosomal familial YOPD. aSyn pathway. |
Turnover
| Sample | results | ||
| Wang 1974 | Rat liver | Double isotope technique | All of the proteins (soluble, lysosomal membrane) have half life of about 4 days. Beta-glucuronidase show 29 |
Machine Learning
- Dimensionality reduction
- Random Forest
- 랜덤포레스트 모델은 결정나무를 기본 모델로 사용하는 앙상블(Ensemble) 방법입니다.
- 다시 말해서 결정나무(Decision Tree)를 여러개 만들어서 그 결과들을 종합적으로 고려하여 결론을 도출하는 방법입니다.
- 예를 들어 집단지성을 통해서 결론을 도출할 때 한쪽에 치우치지 않은 더 좋은 결론을 도출해낼 수 있는 것과 비슷한 원리라고 생각하면 될
- 앙상블(Ensemble) 방법이란?
- 강력한 하나의 모델을 사용하는 대신 보다 약한 여러개의 모델을 조합하여 더 정확한 예측을 해주는 방법입니다.
- 대표적으로 랜덤포레스트, XGboost, Light Boost등이 있습니다.
Magnetoencephalography (MEG)
- Principle
- {Singh, 2014 #2464}
- PD
- Systematic review
- {Boon, 2019 #2466}
- Systematic review
Maiko Tanaka
| RK2 BD available? | ||
| 1K1 GT? | ||
| 2104 | MSA clinical: HorC MSA | CSf (& serum) NFL, vMRI, DATScan, UMSARS (& its components) progression, There are other registries. Hidenao Sasaki (retired |
| MSA preclinical | Poewe mice is too fast to assess aSyn spreading, then what other method available ? | |
| aSyn PFF mice model | Great achievement! |
Metabolomics
| {Network-Rodriguez, 2023 #2347} 원문 not found | PPMI, n=629 | plasma | LC-MS | Results replicated predicted PD associations with ergothioneine and caffeine metabolites and GBA associations with glucosylsphingosine (GlcSph). LRRK2 status was uniquely associated with increases in circulating levels of docosahexaenoic acid and other lipid classes containing DHA including lysophosphatidylcholine (LPC) and bis(monoacylglycero)phosphate (BMP). Additionally, modest but highly specific association between decreased 4-trimethylaminobutanal (TMABA; protein lysine-derived catabolite) and GBA status. |
| — | ||||
| — | ||||
| — | ||||
| — | ||||
| (Langston, 2018 #647) | review |
Milestones (process)
| L identification | L optimization | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| la | T entry | LG entry | PE (PRC1) | Drug-like molecule | CN | CS | CDE (PRC1) | IND | ||||
| la | Hit finding | L generation | L optimization | Pre-CS | DC | |||||||
| la | 9-15 m | 6-12 m | 6m | 9-12m | ||||||||
| demonstrated the concept by use of tool compound | non-clinical target engagement → chemotype selection (eg. 3 chemotypes selected) | in vivo PoC (preliminary) PK/PDrelationship ⇨ Candidate | ||||||||||
| Cell pharmacological/physiological data (Eg) a takeda compound tested in iPS cells for localization of TDP3) | in vitro/in vivo pharmacological validation in vitro tox, ADME, PK-PD | Solid PK prediction generated | ||||||||||
| 5 day tox, | 2w tox,CV, | GLP tox | ||||||||||
| Target is right (confirm the validity of the target) | Compound's POM, Concept validation, 20200 Ceri: ROA and dose are not important. Eg. ICV or 100mg/kg is | Compound improves the disease! | The compound is solid (tox etc) | The compound can enter clinic! |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Top BMP figures | three multi-panel dataset graphs (PTV.IDS Brain BMP, PTV:PGRN Brain BMP at 24/96 hrs, PTV:PGRN CSF BMP at 24/96 hrs); axis labels, group names (WT Saline, KO Saline, KO 798, KO 795, Vehicle, IDS, ETV:IDS), and significance asterisks were transcribed where legible. | partial figure caption legibility; numeric Y-axis values are too small to read precisely. |
Sato Shuji bullet sub-bullet | reads Can GBA Team just use the sam with the trailing word truncated at the column edge in the photo. | trailing characters cut at column edge. |
Turnover / Wang 1974 results cell | reads All of the proteins (soluble, lysosomal membrane) have half life of about 4 days. Beta-glucuronidase show 29 and continues off-photo. | trailing number and unit cut at right edge of slice. |
Metabolomics / Network-Rodriguez citation key | reads {Network-Rodriguez, 2023 #2347} 원문 not found; the leading Network- token is partially obscured by a column boundary. | citation-key reconstructed from visible fragments. |
Milestones (process) table | uses color banding (light-blue header band, beige body band) and the table continues to next photo 20240722_183429. | row order is preserved but some cell boundaries between adjacent process steps are ambiguous in the right-most columns. |