20240722_184300

Upcoming presentations	- SDIB: Thu 2/18/2021 9:00 AM - PRC1 meeting: Thu 3/25/2021 9:00 AM
Team Document share folder	Upstream folder: https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/GBA%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx Regular team meeting: https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/GBA%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT-RAD-Pipeline%2FGBA%20Gene%20Therapy%2FShared%20Documents%2FMeeting%20Minutes%20and%20Material&View=%7B1B8576D4%2DAC80%2D4732%2D874F%2DBADCD0EBF378%7D PRC1 preparation: PRC1 Narrative link folder.
PRC1 narrative	s concern: TM might delay asset progression (what BM is Critical?, what is already feasible vs requiring de novo development) Reduce the amount to half! Steve will review TM section NHP aSyn model: TWO AAVs might be risky, practical
Any others?

	What Jaewon shared on Sharefolder
GBA PET	Jaewon's PET handover document etc
aSyn PET	Most recent email with Onishi's slides
PK/PD	DMPK's slides
TM slides	- Jaewon's most recent TM presentation at team meeting ('GBA GT translation 20201119') - Team presentation slides at sDIB for LGE (20200703) - Others
PRC1 narrative	- The recent version that team has sent to Ceri for his 2^nd time review (version 8) - Laura's review (version 6)
Upcoming presentations	Jaewon has forwarded the meeting invitations of below. - SDIB: Thu 2/18/2021 9:00 AM - PRC1 meeting: Thu 3/25/2021 9:00 AM
Team Document share folder	Upstream folder: https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/GBA%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx Regular team meeting: https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/GBA%20Gene%20Therapy/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT-RAD-Pipeline%2FGBA%20Gene%20Therapy%2FShared%20Documents%2FMeeting%20Minutes%20and%20Material&View=%7B1B8576D4%2DAC80%2D4732%2D874F%2DBADCD0EBF378%7D PRC1 preparation: PRC1 Narrative link folder.

GBA activity CSF, Plasma, NDE		Commercial clinical kit Already available, (blood), we still need to develop for CSF (preclinical and clinical studies?)
GBA m RNA NDE	GT	BFA in Q3 fy2020
GBA protein CSF/plasma	GT	BFA in Q3 fy2020
P-Asyn SIMOA (ADX neuroscience)		BTV in Q3 fy2020
Oligomeric aSyn CSF/Plasma (RT-QUIC/PMCA)		BTV in Q4 fy2020
BMP		- DMPK: Method establishment done by following Denali's protocol - Detection of synthesized internal standard will be tested with cyno matrix
GlcCer & GlcSph		- DMPK: Method estab-lishment done
Lysosomal PD markers		There is some uncertainty & gray area (with ARNU), we should have alignment within NSTM, we may as well take the lead. Alignment on PRC document. Do we need a research proposal?
PRC1 narrative		GBA Activity for patient stratification

Organoids

(Jo, 2021 #1759) Korea + Singapore

Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Syn Mutations

Outcome measures

Original UPDRS (1987)

Part	name / description		progress	MCID
I	mentation	Only 4 questions: intellectual impairment, thought disorder, depression, motivation
II
III	) motor examination (18 items), = 'Motor subscale'	(clin)ician-scored monitored motor evaluation, Tremor akinesia and rigidity axial features	Total score: 108	(Shulman 2010 #567 study). A minimal CID 4.1 to 4.5 on the UPDRS total score. A moderate CID was 8.5 to 10.3 on the UPDRS score. A large CID was 16.4 to 17.8 on the UP-DRS total score. Horvath 2015)^2nd: - 5, - 2.3-2.7,
	(Shulman, 2010 #567, used in (Takeda's Digital PD study). A minimal CID was 2.3 to 2.7 points on the UPDRS motor score A moderate CID was 4.5 to 6.7 points on the UPDRS motor score A large CID was 10.7 to 10.8 points on the UPDRS motor score Horvath 2015)^2nd: - 5, - 2.3-2.7,			(Hauser, 2011 #2646) 4.9 motor score
	- 2 for improvemt & 0.5 point for decline, - -6.2-6.1,
IV	•
V
VI
Total			- Annual change: 8-10/y (Athauda & Foltynie, 2016)

MDS-UPDRS’ = Modified UPDRS (2008)

Conversion: (2018 Simuni) conversion: UPDRS X 1.4 = MDS UPDRS, {Investigators, 2021 #1753} MDS-UPDRS I-III total scores are roughly 30% larger than UPDRS I-III total scores (2.5x for 16 questions in Part 1, 1.1x for 52 questions in Part II, and 1.2x for 108 questions in Part III, yielding a weighted conversion of 1.29x)

MDS-UPDRS (I ~ IV) has a maximum score of 272

	question	(scoring items)
I	13	13
II	13	13
III	18	33
IV	6	6
Sum	50	65

Part	name	description	progression	MCID (minimum clinically Important difference)	calculation notes
I	nonmotor aspects of experiences of daily living (nM-EDL), amp-pd code: https://amp-pd.org/mds-updrs-part1	3.1 cognition 1.2 HALLUCINATIONS AND PSYCHOSIS 1.3 Depression 1.4 Anxiety 1.5 Apathy 1.6 dopamine dysregulation syndrome 1.7 sleep 1.8 daytime sleepiness 1.9 pain 1.10 urination 1.11 constipation 1.12 light headedness on standing 1.13 fatigue 정상: 0점, max 는 52 (Simuni, 2018 #198) in early PD (PPMI, H&Y 1.8 내계산) 평균 5.57 (4.1)	(Simuni, 2018 #198)	2.3p (Investigators, 2021 #1753)
II	motor aspects of experiences of daily life (M-EDL), amp-pd code: https://amp-pd.org/mds-updrs-partII	• self-evaluation of the activities of daily life (ADLs) including 2.1 speech, 2.2 SALIVa & drooling 2.3 chewing & swallowing 2.4 eating 2.5 dressing 2.6 hygiene 2.7 handwriting 2.8 hobbies 2.9 turning in bed 2.10 tremor 2.11 getting out of bed, car, chair 2.12 walking & balance 2.13 freezing , - - - UPDRS II is not acceptable without additional scoring of dyskinesias (2008 EMA guideline) (Simuni, 2018 #198) in early PD (PPMI, H&Y 1.8 내계산) 평균 5.9 (4.2)	13 items. Score range: 0–52	2.4p (Investigators, 2021 #1753)	1. I + I + III: 6.3p (ie 4.9 × 1.29) (Investigators, 2021 #1753) 만약 1.5y 임상기간이라면, 9점 상승하고 (vs baseline. PPMI), 6.3 은 이것 대비 ~70%. effect 는 ~70% slowing 이 필요함. 만약 2y 임상기간이라면, 10.4 점 상승하고 (vs baseline, PPMI), 6.3 은 이것 대비 ~70%. 따라서 drug effect = ~60% slowing 이 필요함.
III	motor examination = 'Motor subscale', amp-pd code: https://amp-pd.org/mds-updrs-partIII	clinician-scored monitored motor evaluation, 18 items. 33 scores. Score range: 0–132 Conversion: (Simuni, 2018 #198) in early PD (PPMI, H&Y 1.8 내계산) 평균 20.89 (8.9), Total MDS-UPDRS score 에서 약 65% 비중 MDS-UPDRS TOTAL score 에서 II+III 의 비중은 83%	- ) at 24 months was 4.28 points (90% CI: 3.45, 5.08) for those with DAT deficit, and 1.12 - points (90% CI: -0.98, 3.1) for SWEDD subjects [53]. - 1.2 p/y ((Athauda and Foltynie 2016, PMID) - (2014 이후 Ahamadi): - 2.0 (6.6) p/y (2016 Davis) from baseline 27.5 (N=675), (Simuni, 2018 #198) observation 몇 년째냐에 따라 달라짐. Eg. 1^st year, 'untreated + treated off', 에서 3.98 p/y (from baseline of 20.89 p), 'treated' 에서 20.89 (8.9) at baseline → 26.52 (10.6) at y1 [sample size calculation] - 20210122_RSLT_GBA GT v2_GP: by Takeda computational biology group, using PPMI data from idiopathic early stage PD (H&Y 1-2), assuming power = 80% and one-…	- 3.25 (for Improvement) ~ 4.63 point (for decline) (Horvath, 2015 #566) - Horvath 2015)^2nd: 2.41 for improvement, 5 point	2. (An improvement of 7.1 points is considered clinically meaningful. https://www.fiercebiotech.com/biotech/anavex-s-neuro-drug-slows-decline-parkinson-s-disease-as-it-boosts-levels-its-biomarker Makkos MCID article Results: Based on the ordinal regression modeling, the MDS-UPDRS II+III, MDS-U…

Uncertain Spans

location	transcription	uncertainty
Original UPDRS Part III row	`(clin)ician-scored monitored motor evaluation`	The leading characters of `clinician-scored` are clipped at the cell’s left edge; the visible substring begins with `ician-scored`.
Original UPDRS Part III MCID column	`A minimal CID 4.1 to 4.5 on the UPDRS total score`	Source repeats `2.3 to 2.7` and `8.5 to 10.3` for two different score scales (motor vs total); the wording is preserved exactly as printed in each cell.
MDS-UPDRS Part I description bullet	`3.1 cognition 1.2 HALLUCINATIONS AND PSYCHOSIS`	The first numbering jumps from `3.1` to `1.2`; both forms are visible in the source as written.
MDS-UPDRS Part III progression cell	`1.12 - points (90% CI: -0.98, 3.1) for SWEDD subjects [53]`	The minus sign before `points` is set as a hyphen-minus in the source and is kept verbatim.
MDS-UPDRS Part III MCID column trailing line	`5 point`	The last token in the MCID cell appears as `5 point` (singular) and may continue on the next page; the cell ends without a closing punctuation in the visible crop.

JS PD KB

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