AAV biodistribution evidence, ICM delivery comparison, and start of intra-parenchymal slide

NHP AAV9 biodistribution evidence (top of capture)

Ref	Species / Serotype	Notes
WorldSymposium 2021	NHP, AAV9	Major Organs Uptake (%ID/g) vs Time post administration (hrs); legend: Left kidney, Right kidney, Heart, Lungs, Spleen, Muscle. Y axis ticks 0.00% – 0.30% in 0.05% steps; X axis ticks 0, 20, 40, 60.
{Hüser, 2017 #1615}	AAV2, Human	AAV2 normaly reside in PBMCs, particularly Tcell, possibly resulting from respiratory transmission during childhood. 243 healthy blood donors, 34% were found to be AAV positive, predominantly AAV type 2 (AAV2) (77%), AAV5 (19%), and additional serotypes. (AAV9 은 거의 미검출)

two candidate tissues : muscle and PMBC.

M biopsy : needle biopsy, not very invasive (stitch? )

Q : how much of AAVs with neuronal-specific promoter actually gets into neurons and other cell types,respectively in vivo?

NHP biodistribution study (GBA GT) will enable us to decide between m and PBMC.

	Major hypothesis	Gap/qestion	How to solve
		Does human have deficit?
		Transduction rate?
PBMC transduction: O		No data	GE PBMC
m transduction: O		{Haurigot, 2013 #1613}{Hinderer, 2018 #1614}WorldSymposium 2021	NHP study : current GBA GT protocol: muscle O, PBMC X

Administration Via Intra-cisterna magna (ICM) Allows Early Intervention To PARK2 PD Patients Less Invasively

Thanks you for invaluable information, Sarah

ROA	Invasiveness	Brain expression / Brain distribution	Toxicity in brain	Toxicity in peripheral organ	Neutralizing antibody (Anti-AAV Ab)*
(1) Intraparenchymal	High	High / Limited diffusion	High	Low	No/Low
(2) Intra-CSF
(a) Intra-cerebroventricular (ICV)	High	High / Widespread diffusion	High	Low	No/Low
(b) Intra-cisterna magna (ICM)	Mid (minimal)	High / Widespread diffusion	Low	Low	No/Low
(c) Intra-thecal (IT)	Mid (minimal)	Low / Limited diffuison	Low	Low	Low
(3) Intravenous (IV)	Low	Low	Low	High	High

Lumber intrathecal microcatheter delivery to cisterna magna

DOI: 10.1089/hum.2016.087

*In clinical trials: Anti-capsid antibodies detected but had no effect on treatment outcomes even after 5y follow-up doi: 10.1126/scitranslmed.3003454

ICM delivery is our first priority for PARK2-PD treatment.

Mol Ther. 2020 Feb 5;28(2):411-421

41 | Parkin GT | Oct 23, 2020 | Confidential - for internal use only

Intra-cisterna magna (ICM) delivery is tested in current clinical trials

Indication	Stage	AAV Serotype	Tx Payload	Dose	RoA	Sponsor	Ref
GM1 Gangliosidosis	Natural History Study NCT04041102	AAV9	GLB1 AXO-AAV-GM1	1.5 x 1013 vg/kg 4.5x1013 vg/kg	ICM	Axovant NHGRI	(see Weismann et al 2015 Hum Mol Genet from Miguel Sena Esteves)
GM1 Gangliosidosis	Ph1/2 planned for Q4 2020 Rare Pediatric Designation	AAV9	GLB1 PBGM01		ICM	Passage Bio
PD-GBA	Phase I/2 enrolling NCT04127578	AAV9	GBA1 PR001		ICM	Prevail Tx	Uspenskaya et al 2020 Neurology
Gaucher Type 2	Phase I/2 Not yet enrolling NCT04411654	AAV9	GBA1 PR001A		ICM	Prevail Tx
Alzheimer's Disease	Ph1 NCT03634007	AAVrh10	APOE2	8.0 x 1010 vg/kg 2.5 x 1011 vg/kg 8.0 x 1011 vg/kg	ICM	Weill Medical College of Cornell University	Rosenberg et al 2018 Hum Gene Ther Clin Dev
MPSI	Phase I/2 NCT03580083	AAV9	IDUA RGX-111	1x1010 GC/g brain mass 5x1010 GC/g brain mass	ICM	RegenxBio	Hinderer et al 2016 Hum Gene Ther
MPSII	Phase I/2 NCT03566043	AAV9	IDS RGX-121	1.3x1010 GC/g brain mass 6.5x1010 GC/g brain mass	ICM	RegenxBio with Esteve/UAB	Motas et al 2016 JCI insight

42 | Parkin GT | Oct 23, 2020 | Confidential - for internal use only

Intra-Parenchymal Delivery

	Good	background resource:
	https://www.youtube.com/playlist?list=PL_3eaar8aMhlsZk5EEq-qikl-JT1AC86K

ROA	Invasiveness	Brain expression / Brain distribution	Toxicity in brain	Toxicity in peripheral organ	Neutralizing antibody (Anti-AAV Ab)*
Intraparenchymal	High	High / Limited diffusion	High	Low	No/Low
Intra-CSF
(a) Intra-cerebroventricular (ICV)	High	High / Widespread diffusion	High	Low	No/Low
(b) Intra-cisterna magna (ICM)	Mid (minimal)	High / Widespread diffusion	Low	Low	No/Low
(c) Intra-thecal (IT)	Mid (minimal)	Low / Limited diffuison	Low	Low	Low
Intravenous (IV)	Low	Low	Low	High	High

	Major hypothesis	Gap/qestion	How to solve

R, TREM2 SM, tau suppressor (phenotypic screening), stathmin2 (FTD)

TAC for LRRK2, PD Symptomtic (internal 에서 만들려, 크리스틴보햄? 관심)

nition 은 안 할 거다.

Uncertain Spans

location	transcription	uncertainty
Bottom-of-capture text	nition 은 안 할 거다.	leading nition is the visible tail of a Korean-language word that begins above the photo edge (likely cognition / recog­nition family); only the suffix is in this capture and the preceding context is cut.