20240722_184237

Pipeline				Caraway (lead optimization) for GBA-PD
Outcome measure
Animal model				Elevated gastrin and cellular vacuolization have been confirmed in the Mcoln1-/- mice [13],
Biomarker-established				Gastrin? (js: there is no clear statement that gastrin is a BM in this condition) Lysosomal pH & vacuoles (fibroblast)?
BM-new				(Vardi, 2021 #1718) (n=1) (patient postmortem brain & csf, mouse model brain & CSF) ↑ calbindin2 in patient & mouse description from brain tissue though), ↑ CTSA/B,D/H (in human cerebrum, cbll, CSF, note that these are proteins not activity) NCT02298673 (MS-based, blood, ongoing?)

Multiple Sclerosis

IL-1b

CSF
Cacabelos 1991 (no text) 명확한 언급, but 안 증가라는 듯	Blood Kallaur 2013 (원문)
(Rossi, 2014 #1886) ack of association between prospective disease activity and cerebrospinal fluid IL-1β level at time of remission
(Rossi, 2014 #1886) 2^nd, We have previously shown enhanced free IL-1β levels and IL-1β-mediated neurotoxicity in the CSF of patients with active MS and Gd + lesions [13]
(Rossi, 2014 #1886) table5: 안 증가인듯

Natalia Boukharov

Communication: Outlook> RD DDU > Translational Sciences

	D409V인 쓰는 이유? GLCsPH 올리시?
	그래도 D409V에서 Histology에 줄수 있니?
Acid ceramidase i	GlcSph감소 정도 monthl report에서 확인.

From: Boukharov, Natalia <[email protected]>
Sent: Wednesday, December 30, 2020 12:56 AM
To: Lee, Jae Won <[email protected]>
Subject: RE: Translation for nGD

Dear Jaewon,

Happy New Year!

I would like to update you on the Gaucher mouse models status. As I mentioned, I have recently reviewed data for L444P, N370S and D409V mouse models currently available at RD DDU as well as literature on these and other Gaucher models. I have presented my findings to the RD DDU Gaucher SMA team. The team has decided to use L444P for routine compound screening (l444p 가능 줄 비) GlcSph 거의 없는데도, 13.2%라도 줄였기 때문에?) (because rhGCB increased brain GlcSph in D409V mice?). Read-out will be activity in the brain and visceral organs and substrate reduction in the liver. At some point we will age a cohort of L444P to test substrate reduction in the brain by lead candidates.

The team has carried-out natural history studies for all three lines. Unfortunately, due to budget constraints, collected samples will not be analyzed until next budget year (~April-May 2021). But regardless, based on in-house data and published reports neither L444P nor N370S will work in the pupillary light reflex test (because neither shows significant brain GlcSph?). Older D409V mice have some CNS abnormalities and could theoretically have ocular abnormality. But, if I understand correctly, since D409V is a mouse gene mutant, it will not work for your compound (we have terminated GBA activator project). Acid ceramidase inhibitor project will use D409V mice for POC in GD).

On the bright side, I found a paper where pupillary light reflex was used in Gaucher clinical trial (attached). It seems quite sensitive. I also attached nonclinical study referenced in the paper. They did not use Gaucher mouse models. Robust activity increase in mutant cells and slight activity increase in normal seems to have translated into good clinical pupillary response. With this “proof of translatability”, similar data package for your compounds could be enough to propose pupillary light reflex as an exploratory clinical endpoint.

If you are interested, we can schedule a call after January 4^th and I would be happy to walk you through the data we have for different mouse lines and current in-vivo testing plan. Kind Regards, Natalia

NDU, DDU Subteam

20201022 Kick off

Enablers (translational biomarkers) Differentiation strategies Dec is important What kind of biobank (current & future)

Investment request for what, when and why
Good resource: translational tools timeline (by disease area)
Wave:
- 1
- 2
- 3
WHY MSA?
ME: wave 1, team
- Tau & aSyn
  - NSTM strategy
- ACHIEVEMENT strategy
- Lyso & mito are wave 2
- My role: ePOC?

Sharefolder


20201022 DDU subteam Kick off		NDU_DDU_subteam_kickoff_20201015. https://mytakeda.sharepoint.com/sites/NeurodegenerativeDisordersUnit/ https://mytakeda.sharepoint.com/sites/NeurodegenerativeDisordersUnit/
Clin Q
Extended		https://mytakeda.sharepoint.com/sites/NeurodegenerativeDisordersUnit/
NDU strategy document		https://mytakeda.sharepoint.com/:w:/r/sites/NeurodegenerativeDisordersUnit/Shared%20Documents/1.%20NDU%20Related/1.%202023%20FY%20Q3%20Strategy%20Update/NDU%20Strategy%20document%20(2023%20FY%20update).docx?d=w0ab03f481b52436ba4142507014c4b6f&csf=1&web=1&e=RwcMCe
20201105 DDU subteam 1^st f/u		https://teams.microsoft.com/_#/pptx/viewer/teams/https:~2F~2Fmytakeda.sharepoint.com~2Fsites~2FNeurodegenerativeDisordersUnit~2FShared%20Documents~2FDDU%20subteam~2FDDU%20Subteam%20meeting~2FMeeting_20201105_DDU%20future%20image%20of%20Targets%20and%20Modalities_Integration.pptx?threadId=19:[email protected]&baseUrl=https:~2F~2Fmytakeda.sharepoint.com~2Fsites~2FNeurodegenerativeDisordersUnit&fileIds=ca8-d0bc-4e6a-a236-d2df6badbaff&ctx=files&rootContext=items_view&viewerAction=view
20201111 Extended NDU meeting	PD	PD: near term objective: Early development strategy, provide support to TAK-341, ONGOING Timeline Rare to common, ask for resource AMP-PD Phenotypic, Peter maycox
20201119 ddu subteam
20210209	Jaewon	[GBA] TE ? GBA PET, GBA protein/mRNA GlcCer/GlcSph lysosome [Parkin] TE: Parkin protein/mRNA ? Ps65ub MC1
20210209	Steve	aSyn

Rare → common



enabler aSyn
enabler	Retinal aSyn GBA-LBD vMRI Natural Hx Mitochondria integrity Mitochondria function
death pathway	Genetically-defined patient mechanism-based patient slection in sPD

inflammation

	stage	Disease (target patient)	Competitor	Differentiation
SNCA sASO	PE	PD/MSA	Ionis/Biogen	Stereopure (biodistribution and retention)
SNCA HDO	LG			Systemic injection (easy to ad.)
SNCA degrader	Target entry			Systemic injection (easy to ad.)

Uncertain Spans

location	transcription	uncertainty
Multiple Sclerosis MOA grid	(empty 4-column placeholder)	The MOA grid is rendered with blank cells in the source; preserved as empty `<td>` cells.
Natalia email body Korean parenthetical	`(l444p 가능 줄 비)`	Korean shorthand reading is unclear; OCR returns the same string twice but it may be `l444p로 가능 줄임` or similar, preserved verbatim.
Pipeline overview bottom rows	`Disease (target patient)` and `Competitor` columns	Rows for HDO and degrader have empty Disease/Competitor cells in this capture; they may be filled on subsequent rows continuing on the next page.

JS PD KB

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