Rare Disease Prevalence, Lysosomotropic / LAMP1 Binder, Postmortem Lysosomal Evidence

Rare-Disease / Prevalence Table

band	disease	col-3	note	col-5	col-6
	GBA-PD	1	US: 1 Mil 의 10% → 100,000 (200,000 보다 적으니 rare disease 이긴 하네)	300	1 million in US
common	CMT1	1		2,500
	AGS	1-5	orpha.net/consor/cgi-bin/OC_Exp.php?Expert=51&lng=EN	10,000
	FTLD-Tau	1	5–7 per 100,000 (Bahia, 2013 #21): 위와 유사해야하는데, Daria: 10-20/100,000 (theoretical genetic prevalence of biallelic carriers) 로 휠씬 더 많음. 이러면 EPOP 35,000-70,000 WW.	20,000	5-7 / 100,000
	PRKN-PD	1	Group (age ≥ 18) Biallelic PRKN mutations Monoallelic PRKN mutations with symptomatic PD in general populationa with symptomatic PDb United States and Europe 23,000-70,000 1,622-13,000 33,000-45,000 United States 10,000-30,000 930-7,400 19,000-26,000 Europe (EU + UK) 13,000-40,000 692-5,500 14,000-19,000 Japan 40-107 NA NA China 420-1,100 NA NA US and Europe has been estimated to be 1,622-13,000 -19k-36k patients with biallelic PRKN mutations across the US, EU4+UK, China, and Japan	25,000
	HD	1		40,000
	GBA-PD SEVERE MUTATION		10% of GBA-PD , then 0.003% in population , ie 3/100,000 1-9 / 100 000	100,000
	Krabbe disease	1		100,000	1
	Niemann-Pick disease Type C	1			1
	PD with pathogenic GALC variant	1		150,000 (0.2% of PD, ie 300x500)	3
	CAPS	1		360,000	2.5
	GD type 3 (nGD)	1		2,000,000	100,000
rare	Late onset Krabbe disease	1		1,000,000

PET

Lysosomotropic vs Lamp1 Binder

	Lysosomotropic	Lamp1 binder
Goal	20231009 Bambos: to image the abundance of lysosomes primarily in the brain and in some peripheral organs. The goal was to use them in Gaucher, Hunter, and San Filippo.	TR06800430 becomes the new most potent compound Top three: TR06799625 and TR06805975 (are much more potent than the starting point TR01579971), TR06797649 with Kd: 0.5 uM). TR01579971 TR01465129 TR06327971 TR06320341 TR06282607
Compounds	Three compounds have promising in vitro & in vivo : (TR06795533, TR06795793, and TR06795792) TR06795973 has all the desired profile needed for a lysosomal PET tracer, so far. The remaining studies for this compound to progress towards a candidate are the safety study and biodistribution study of 18FTR06795793.
Challenge/Questions	Include PET proposal in PE proposal Js: in vivo imaging study with 18FTR06795793 charactetrization (time course)→ Tx effect , in both GD and PD animal models (GD 에서는 D409V mutation , PD 에서는 A53T (+CBE)로 Pathogen 이 상이하니 lysosome 의 상태가 다를것이기 때문에 두 model 다 필요) . When: 가지고 있다가 CN molecule 성해지면 (2025 Feb)	- The project is still in the early : Hits identification and confirmation.   : Current hit: permeability/efflux is ok, but Kd is 0.5uM
principle	(Kuzu, 2017 #2489) Weakly basic amine compounds that induce rapid vacuolization of cells are known as lysosomotropic molecules [1-3]. "Lysosomotropism" was first introduced by de Duve et al. to define compounds that accumulate up to several hundred-fold higher concentrations within the late endosomal/lysosomal (LE/L) cell compartments [1]. Weakly basic compounds, depending on their lipophilicity, can readily diffuse through the limiting membrane of acidic organelles in their unionized form and get protonated (ionized) in the acidic lumen (Fig. 1). Due to their decreased membrane permeability, protonated molecules cannot cross-back to the cytosol, hence get trapped and accumulate inside the acidic lumen (also referred as ion trapping) [4]. Although they have diverse structures, most of the lysosomotropic compounds harbor an amine group that is responsible for their weakly basic properties. The degree of ion trapping depends on pH of the cellular compartment as well as physicochemical properties of the compound such as pKa (acid dissociation constant) and membrane permeability.	Less priority than lysosomotropic, because: In vitro assay worked x, Cholesterol binding. Selectivity issue: LAMP1 in golgi, → To revisit.
20231018	Fluorinated?, In vitro and in vivo with the two compounds. TR06795793, and TR06795792 In vivo: ↑ brain uptake in WT vs Hunter mouse, LC-MS based colde study done. Used Chinese CRO Prioritized lamp1 because of ↑ dynamic window (bigger compartment),
	Selectivity issue: other acidic intracellular organelle,

Postmortem Human Lysosomal Evidence in GBA-PD

GD dropped.
No definite
Human evidence: Postmortem studies are not abundant, however, the findings indicate altered lysosomal density (increased biogenesis and/or accumulation of damaged, enlarged lysosomes) and impaired autophagy.

Author	Sample #	Brain region	Results
(Kurzawa-Akanbi et al. 2012, PMID)	GBA-PD: n=21	Frontal, cingulate	↑ LAMP1, ↑ LAMP2, ↓ Cathepsin D activity
(Gegg et al. 2012, PMID 23034917)	GBA-PD: n=4	putamen	↑ (trend) LC3II
(Li et al. 2019, PMID 30160596)	GBA-PD: n=6	Cingular cortex	↑ LC3II, ↑ SQSTM1, =LAMP1, ↓ p-MTOR, ↓ p-RPS6, ↓ AMBRA1, ↓ BECN1
(Moors et al. 2019, PMID 29948939)	GBA-PD: n=3-7	Frontal cortex, SN	↓ (trend) Cathepsin D activity

pH evidence ? is it possible to measure it in postmortem ? then how to de-risk? → CSF lysosomal BM result?
Animal model: best to represent GBA-PD patients, then GD model x?

REM Sleep Behavior Disorder

(REM sleep behavior disorder)
nptom
 o the loss of muscle atonia during REM sleep and dream enactment,
dence

	GBA+PD+	GBA-PD+
REM sleep disorder	No difference		(A. Siderowf, 2019) 82 GBA+PD+, 366 GBA-PD+

PSYCHIATRIC OUTCOMES IN PD

Uncertain Spans

location	transcription	uncertainty
Rare-disease prevalence column-3 vs column-5	numeric mapping of 300, 2,500, 10,000, 20,000, 25,000, 40,000, 100,000, 360,000, 2,000,000, 1,000,000 to row labels	Original source uses adjacent narrow columns; a few rows may shift by one row when the cell band visually merges.
Rare-disease last col	5-7 / 100,000, 1 million in US, 2.5, 100,000 etc.	Right-most numeric column is partly cropped at the right edge in some rows.
Lysosomotropic compound IDs	TR06795533, TR06795793, TR06795792, TR06795973	The compound IDs TR06795973 vs TR06795793 appear in close succession; the digit 7 vs 9 differs by row but small text causes occasional ambiguity.
20231018 row	LC-MS based colde study	The token reads visually as colde (likely a cold typo in the source); transcribed as written.
REM sleep table left header band	left-most empty header cell	The leftmost cells of the small REM sleep disorder row may be a row-label column rather than empty; the visible image shows a colored band but no readable label.