Scenario / Disease-Model Questions, Safety De-Risking Strategy, Sharefolder, Parkin Protein Notes, And Assays Table
| Scenario의 개념 (least robust – most robust) | Is disease model necessary? | |
|---|---|---|
|
- 정상인의 brain parkin protein level 이 A (Soon NSTM will define this) 라면, - NHP 연구를 통해, 이것을 달성시키는 Dose B를 define 히면 이것이 그냥 HED 아닌가? Dose B를 nhp 에 주었을 때의 CSF parkin level 이 C 라면, 임상에서 csf C 로 확인하면 되지 않나? Disease model 은 neuroprotection과 연결시켜서 노랑을 strengthen 시킬 수 있을 것. | ||
| Is a PD marker necessary? | (특히 disease model이 없다면), PD change 로 노랑을 strengthen 시킬 수 있을 것. | |
| NHP 1M BD study | How many doses? | |
| • | ||
| • | ||
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Safety
| MOA | Frequency | Consequence | In vitro | translatability | De-risking strategy (preclinical) In vivo / translatability | BM | Route? | Monitorable? | Clinic Manageable? | BM | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GT-general | imunogenecity | Capsid | Common | ↓ efficacy, ↑ cytotoxicity | Should be evident in vivo studies Unclear | ? | ||||||||
| transgene | Common | Efficacy, safety (cytotoxicity) | In vivo studies unclear | |||||||||||
| DRG degeneration | UPR → inflammation → cytotoxicity | Capsid/transgene | Not common (almost universal in NHP) | Cytotoxicity (DRG) | UPR gene expression analysis | UPR gene expression analysis | Neurosurgery | |||||||
| Parkin-specific | ↑ DA neuronal loss in SN | Transgene | Check the effect in DA neurons (pharmacology) Histopathology of brain in relatively long-term (3 months or more) NHP biodistribution and tox studies | Neurosurgery | Js; DATScan? | Js: not manageable | ||||||||
| ↑ mt density in muscle | transgene | Neurosurgery | ||||||||||||
| Muscle hypertrophy | transgene | middle | Histopathology of skeletal muscles in NHP biodistribution and toxicology studies | Neurosurgery | Js: m biopsy? | Js: manageable (recoveralbe) | ||||||||
| Parkin-specific | ↑ fibrosis in heart ↑ Parkin → ↑ calcium dysregulation → cardiac hypertrophy | transgene | middle | Histopathology of heart and lung in NHP biodistribution and toxicology studies ECG/Echo in biodistribution and exploratory toxicity study | ECG/Echo 겠네 | Neurosurgery | Js: ECG/Echo | Js: manageable (recoverable) | ECG/Echo 겠네 | |||||
| T-general | Genotoxicity (unwanted insertion of transgene DNA into host chromosome) | Not common | tumor | FDA is no longer concerned. | ||||||||||
Sharefolder
- Mouse poc study 에서 BM? → DMPK 와 논의하자
- 내 생각: MC1 ARG IN MICE POC study or NHP BD study?
[https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/Parkin%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT%2DRAD%2DPipeline...]
[https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/Parkin%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT-RAD-Pipeline%2FParkin%20Gene%20Therapy%2FShared%20Documents%2FMeeting%20Minutes%20and%20Materials&FolderCTID=0x0120007803EDB3EB43F94B88445EA2823B1719&View=%7B1B1D5A2D%2D5E8C%2D41AB%2D978F%2D618DC69212AC%7D]
Timeline
[Parkin GT Scenarios and Timelines.pptx]
Resources: my PGRN in this document
- Parkin protein:
- Parkin KO mice
- Sensitivity, linearity, stability, selectivity
- Human pooled CSF → PD Patient CSF
- Check cross-reactivity to mouse parkin (although we will need to measure only human parkin)
- MPTP study에서는, mice parkin 이 많이 있으므로 구분해야 할 것.
- How?
- MPTP study에서는, mice parkin 이 많이 있으므로 구분해야 할 것.
Option 1. Mouse Brain homogenate에서 detectability 확인 (이거라 함) Option 2. 위 과정 없이 바로 CSF 측정 Option 3. Mouse CSF 에서 detectability 확인 (right after we confirm detectability in human CSF)
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How long does it take?
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Questions
- Who analysis brain pS65Ub?
- Can we freeze mouse CSF and measure when our assays are ready?
- May be feasible, caveat is that we don’t normaly test longterm stability
- What does it take for the assay to be ready for mouse studies?
- Parkin BM timeline 등 자세히 없으니 만들자
- Confidence 측면에서) asset generation timeline 과 맞춘다
- Resource prioritization 필요함.
Assays
| Assay | Buffer LLOQ | Concentration note | NBB result-CSF | CSF | Required volume |
|---|---|---|---|---|---|
| Parkin | 0.061 pg/mL | 10 times concentration from 1 mL |
n 7 Minimum 0.7 Maximum 2.500 |
NBB sample For 1ml, 1.3/0.061 pg/ml = 21x (this is window), For 500ul LLOQ is 0.12 pg/ml, so then window is only 11x. | 1.5 mL 이라는데? |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Safety table column structure | the wide multi-column header / sub-header arrangement | The De-risking strategy block visually splits into “preclinical” (In vivo / translatability / BM) and “Clinic” (Route? / Monitorable? / Manageable? / BM) groupings; column boundaries between these groups are best read from the body_full and derisking_table evidence images. |
| Sharefolder URL #1 | trailing path is wrapped and truncated by the photo edge | The first SharePoint URL ends mid-path (...Pipeline...); preserve only the visible portion. |