Pipeline of GD & GBA-PD

PR001 Mouse Data: 4L/PS-NA Genetic Mouse Model

Levels of insoluble alpha-Synuclein in the 4L/PS-NA genetic mouse model were quantified by enzyme-linked immunosorbent assays, or ELISAs, an analytical biochemistry assay.
 
그런데, 이래는 똑 같은 aSyn data인데 dose가 다르네?
 
PR001 decreased alpha-Synuclein accumulation in the genetic mouse model

Insoluble alpha-Synuclein
alpha-Synuclein Ratio
Control + vehicle
4L/PS-NA + vehicle
4L/PS-NA + 1.3E+?? vg PR001

source field	transcription
model / condition	GBA+PD
mutation / induction note	D409로 ind열었다는데
model	CBE + A53T Mice, 9-10 w old
timing / endpoint note	ICF 겨우 3주후에 죽여서 보았네?!
effect note	↓ a-syn

PR001 Mouse Data: A53T + CBE Model

원래 A53T mouse model does not exhibit widespread a-Syn pathology in the brain, 그래서 CBE 섞음
그런데, 아래는 같은 model, 같은 data 인데, 다른 dose
 
PR001 - Reduced HMW alpha-synuclein aggregates in A53T mouse model treated with CBE
 
PR001 efficacy study in alpha-Synuclein transgenic mice treated with CBE
PR001 suppressed high molecular weight alpha-Synuclein accumulation in transgenic mice treated with CBE
Prevail ASGCT 2020 presentation

group	transcription
No PR001, no CBE	vehicle only, n = 4
No PR001 + CBE	vehicle only + 100 mg/kg CBE, n = 4
PR001 + CBE	100 mg/kg CBE + 4.3 x 10^11 vg PR001, n = 5
model note	All experiments were performed in A53T mice.
statistics note	Each bar represents the mean +/- SEM.; P value: *p<0.05 by ANOVA followed by Tukey's HSD multiple tests correction.

Dose-Finding NHP ICM Biodistribution

Dose-finding
NHP (ICM)

Vector Genome Heatmap

Vector Genomes per ug DNA tissue

tissue	control	low dose	high dose
Hippocampus	0.00e+00	4.68e+03	5.81e+04
Periventricular Tissue	0.00e+00	5.00e+02	2.17e+03
Putamen	0.00e+00	6.94e+01	1.37e+04
Ventral Midbrain	0.00e+00	1.28e+03	1.51e+04
Cervical Spinal Cord	0.00e+00	1.07e+05	1.62e+05
Thoracic Spinal Cord	0.00e+00	1.54e+05	3.23e+05
Lumbar Spinal Cord	0.00e+00	8.91e+04	2.69e+05

No PR001: vehicle only; Low dose: 2.1 x 10^10 vg/g brain PR001; High dose: 8.0 x 10^10 vg/g brain PR001
근데 위가 아니라 용량이) Prevail conducted 6.2E+10 and 2.3E+11 vg/brain in NHPs (20210224 GBA GT team meeting)

Equivalent to clinical starting dose
No safety signals

PR001 NHP GCase Expression Paragraph

Prevail didn't publish 'cellular transduction data'
The vector genome copy levels, or "brain exposure levels," of PR001 observed in the NHP CNS at 30 days were comparable to the levels that achieved efficacy in our mouse models.
Consistent with widespread vector genome copy distribution, we observed widespread expression of the GCase enzyme encoded by PR001.
GCase levels were quantified using an antibody-based automated assay, SimpleWestern.
Results from cortex, hippocampus and midbrain samples were obtained from NHPs dosed with ICM injection of vehicle only, a low dose of PR001 or a high dose of PR001.
NHPs that received either the low dose or high dose of PR001 exhibited consistently elevated levels of GCase 6m after ICM injection, compared to samples from NHPs that received vehicle only.
The graph below depicts the data across the cortex, hippocampus and midbrain regions, analyzed in aggregate.

-they measured GBA protein level in NHP (ICM) cortex, hippocampus, VM (2020-12-23 Prevail Tx PR001 overview, p28,29)

No PR001: vehicle only; Low dose: 2.1 x 10^10 vg/g brain PR001; High dose: 8.0 x 10^10 vg/g brain PR001
Each bar represents the mean +/- SEM of three NHPs per group.
P-value: ** p < 0.01 by analysis of variance followed by Tukey HSD.

Biodistribution And Safety-Margin Table

row	unit / timing	vehicle only (control)	low dose	high dose
Dose	ICM	0 vg/g brain	2.1 x 10^10 vg/g brain	8.0 x 10^10 vg/g brain
Safety margin (202011 prevail corporate report)				6x safety margin to PD-GBA starting dose; 5x safety margin to nGD starting dose
DNA: biodistribution / vg copy levels / "brain exposure levels"	30 days after	0 Vector copies/ug genome DNA (=ug/DNA tissues)	Eg in frontal cortex: ~1 x 10^2 Vector copies/ug genome DNA	Eg in frontal cortex: ~2.55 x 10^5 Vector copies/ug genome DNA
GBA mRNA			보고 없는 듯
GBA protein level (transgene만이 아니라 endogenous origin과 안 구분한 듯)	6 m after (바로 위 그림)	100% of control	~120% of control (ICM이라서 많이 안 증가하는구나)	~120% of control

Dose Selection Text

The above studies have informed our proposed dose selection for our first-in-human clinical studies.
The efficacy studies in mice helped us identify the level of biodistribution throughout the brain that we predict would translate to efficacy in humans.
Our NHP toxicology studies helped us identify the dose that, when delivered by the intended clinical route of administration (ICM injection) in an NHP, corresponds to the same brain exposure level as the optimal dose in mice.
We then scaled this NHP ICM dose to humans based on brain weight.
This proposed human dose is lower than the highest dose that was observed to be well tolerated in both mouse and NHP studies.

Clinical Trials Of PR001 (=LY3884961)

phase / row	name	target pt	status	number	design	Tx	primary outcome	secondary
P1/1a	PROPEL NCT04127578	GBA-PD; H&Y 3-4 (off), hetero		16	multicenter, randomized, OL, sham procedure-controlled, ascending dose, FIH study		Safety	1. Change in GCase enzyme activity levels in blood | Time Frame: Baseline and Months 3 and 12

Uncertain Spans

location	text/status	reason
navigation path	Pipeline of GD & GBA-PD > Prevail PR001	Inferred from body content and visible navigation headings; the active nav highlight is not clearly visible in the crop.
page label	Page 20 of 28	Apple Vision and PaddleOCR agree broadly, but the page count differs from nearby synthesized pages because the Word status bar may reflect another document/window state.
top PR001 4L/PS-NA block	dose in 4L/PS-NA + 1.3E+?? vg PR001	The dose label is too small/cut off in the asset; preserved as figure evidence instead of exact metadata.
row label	D409로 ind열었다는데	Korean/OCR text is partial and may be shorthand for an induced GBA mutation/model note.
A53T + CBE dose	4.3 x 10^11 vg PR001	OCR is consistent enough for draft, but this is a high-risk numeric dose.
NHP dose note	2.1 x 10^10, 8.0 x 10^10, 6.2E+10, 2.3E+11	Multiple dose bases appear on the same page (vg/g brain and vg/brain); keep exact wording until reviewed.
heatmap values	tissue-level vector genome copy values	Values are visually readable and OCR-supported, but small scientific notation values should be checked before structured KB extraction.
GCase protein barplot	~120% of control; p-value ** p < 0.01	Exact plotted means are not directly labeled; percentages are approximated from visible table/text.
clinical trial row	PROPEL NCT04127578 row	Bottom of photo cuts off the row; secondary outcome text likely continues on the next photo.