Pipeline of GD & GBA-PD

aSyn propagation suppressor (phenotypic screening) (=SMOL)

SNCA BTV (Brain Transport Vehicle: ASO/HDO + transferrin receptor (TfR) ligand): Maeda Ryota (SNCA HDO의 후예)

SNCA-ASO (WAVE)

Program start as the point for formalizing alignment

“Old Portfolio Entry”

Milestone	Target Entry	Program Start ✓	Lead Gen Entry	Portfolio Entry	Candidate Nomination	Candidate Selection	Early Develop Entry	IND	Early PoC
Purpose				Commit to Medicine Discovery		Commit to Clinical Asset	Commit to Medicine Development
Decision Making Body			PRC			RSLT	PRC		PRC
Cumulative Cost	1 oku¥		5 oku¥ 3 oku¥	11 oku¥	21 oku¥	24 oku¥	30 oku¥
Cumulative Time	1-2 yrs		2.0-3.5 yrs	3.5-5.5 yrs	5.0-7.3 yrs	5.5-8.0 yrs	6.5-9.3 yrs

Target Validation → Hit to Lead → Lead Generation → Lead Optimization → Pre-CS → Development Candidate → Phase 1 → Phase 2
 
← 1.5-2.5 years →
←─── 4-6 years from IND ───
←─── 5.5-7.5 years from IND ───

aSyn Degrader

Can we just target pathologic aSyn - (pSyn may not be tractible), oligomeric aSyn/

Native aSyn is monomeric and helical oligomeric

PATIENT selection: all should have all forms.

DLB (amygdala, eg. SPAL)

heterogeneity' PD

{Strohäker, 2019 #1785} there was a greater structural heterogeneity among α-syn fibrils from the PD brain compared (fig6)

aSyn Propagation Suppressor

Native aSyn is monomeric and helical oligomeric

PATIENT selection: all should have all forms.

DLB (amygdala, eg. SPAL)

heterogeneity' PD vs MSA

Mouse primary cortical neurons (arnu) + (mouse) aSyn PFF

(2ndary assay,) (SNCA mutation-derived) iPS-Dopaminergic neuron + (mouse or human) aSyn PFF

MOA

Expected MOA of HIT molecules

Internalization
Extracellular release
 
HSPGs   LAG3   Other Receptors   Receptor clustering
Early endosome
Late endosome
Lysosome
LRRK2 / VPS35 / GBA
Exosome release
Exocytosis of α-syn
nanotube
1st Neuron / 2nd Neuron
PFF neuron
 
Red callouts:
- Extracellular trap
- Internalization inhibition
- Aggregation inhibition
- SNCA/α-syn reduction
- Degradation enhancement
- Secretion inhibition
- Transmission inhibition

Modified from Neurobiol Dis, 2018, 109: 219

Differentiation

Small molecule propagation suppressor is differentiated from other αS-targeting approach

SM propagation suppressor

category	text
Strengths / Differentiation points	SM is an orally available disease modification therapy.
Strengths / Differentiation points	Novel MOA can be targeted by phenotypic assay.
Risks / Issues	Target ID would be necessary for PE or before.

αS mAb

category	text
Strengths / Differentiation points	Prasinezumab (Roche/prothema) has shown a positive sign in the clinic.
Strengths / Differentiation points	Pathology spreading process can be blocked by mAb.
Strengths / Differentiation points	Relatively safe profile is expected.
Risks / Issues	It could be difficult to attach intracellular αS aggregates.
Risks / Issues	BBB penetration is considered low.

ASO/NAM

category	text
Strengths / Differentiation points	Knocking down is a direct approach to reduce amount of αS.
Strengths / Differentiation points	Intracellular αS is affected by ASO.
Risks / Issues	Brain distribution might be insufficient due to intrathecal administration.
Risks / Issues	It might result in side effect by lessening physiological function of αS.

Modified from Neurobiol Dis, 2018, 109: 219

Targets

Targets
some targets from PFF-based screen in mouse primary neuron (Asyn pff in vitro) {Bieri, 2019 #1778}

Uncertain Spans

location	text/status	reason
SNCA BTV row	TfR / transferrin receptor ligand	PaddleOCR reads TfR; Apple reads TTR. Image looks closer to TfR.
Cumulative cost row	okuY / oku¥	Unit glyph reads as Japanese yen ¥; preserved as oku¥.
Cumulative Cost Program Start cell	5 oku¥ and 3 oku¥ overlap	Two values appear in the same column; preserved both as visible.
aSyn Degrader first row	tractible	Visible spelling has tractible; may have intended tractable.
DLB row	SPAL	Three letters small and could be SPAL or similar.
aSyn Propagation Suppressor in vitro model	arnu	Parenthetical token after Mouse primary cortical neurons is small.
αS mAb company	Roche/prothema	OCR variant was prothena; image appears closer to prothema.