20240722_184443

The main sites of ROS production in mammalian cells are mitochondria [69], , in turn,	and its generation is initiated by the electron leak primarily at complex I through partial reduction of molecular oxygen (O₂) to superoxide radical (O₂*-) by a single electron uptake	it leads to either hydroxyl radical (OH*) generation through iron catalyzed Fenton reaction or to peroxynitrite (ONOO−) (Fig. 3).	Superoxide radical (O₂*-) also converted to hydrogen peroxide (H2O2) superoxide dismutase 2	Dopamine in PD brain is oxidized to form dopamine quinones and free radicals either by self-oxidation or by mitochondrial outer membrane bound monoamine oxidase (MAO) such as MAO-A (in neurons) and MAO-B (in glia). [Oxidation products of dopamine may cycle to form aminochrome, and are reactive enough to produce superoxide radicals (?)]

Above mainly 2019 Raza

Evidence in PD

		csf	Blood
(Khan, 2018 #582)
(Wei, 2018 #581)	Looks better than Khan 2018	Nothing is significant

Measurement of OS

	Redox state		Oxidized DNA		Oxysterol
		example		example		Example
	GSH/GSSG ratio, ↓ is stress	Amathus, Rat SN	8-OHdG, ↑ is stress	Amathus, Rat SN	7β-HC, ↑ is stress	Amathus, Rat SN

Route of Administration

ICM (= Suboccipital puncture)

Biodistribution
- WORLDSympsium 2021 Pukenas: 대략, cortxt에 잘 분포함 (deep structure eg. striatum, thalamus, midbrain 시키)
Toxicity
- DRG axonopathy,
- Dorsal spinal column axonopathy
- Inflammatory cell infiltrates

(Sagittal mouse-brain anatomical illustration with labels: Arachnoid mater, Lateral ventricle, Third ventricle, Fourth ventricle, Subarachnoid space, Cisterna magna; CP markers in red. Source: Molecular Pharmaceutics 2018; 15 (3): 911-922.)

→ staggered dosing in every cohort, is recommended (assessment of upper and lower limb somatosensory evoked potential (SSEP)
Examples

MPSII	NCT03566043	RGX-121	ICM
MPS1	NCT03580083	RGX-111	ICV
MPS1	IIS	RGX-111	ICM

Route of administration: Intra-cisterna magna (ICM) injection

Quotes from KOL callouts on the slide:

Ronald Crystal, MD, Weill Cornell Medicine on his ICM approach: “so we decided to do C1 or C2 injection. It’s done under CT scanning, it’s an outpatient procedure, and it takes about 25 to 30 minutes to place the needle, and about 5 minutes to administer. So far, we’ve treated 3 patients” (Nov 23, 2020)
Prof. Jason Sheehan, Vice Chair – Dep. Neurosurgery, Univ. Virginia and performing ICM injection. The procedure is done under sedation and depending on volume can be completed in 45 min with CT scanning. MRI scanning would also work. (Nov 2020)
Robert P. Allen, MD, Interventional Radiologist, Denver, CO is planning ICM injections, experienced in IT and plans to use CT for imaging. Total procedure should be about 30 minutes. He believes that it will become an outpatient procedure.

Confidential - for internal use only

Indication	Sponsor	Stage	AAV Serotype	Tx Payload	No. of patients dosed	Comments
Tay-Sachs, Sandhoff's	Axovant /Sio Gene Tx	Phase 1/2 NCT04669535	AAVrh8	HEXA/ HEXB AXO-AAV-GM2	(2)	Treated under investigator initiated trial No AE reported¹
GBA-PD	Prevail Tx / Lilly	Phase 1/2 NCT04127578	AAV9	GBA1 PR001A	1	No procedure-related complications, well-tolerated
Gaucher Type 2	Prevail Tx / Lilly	Phase 1/2 NCT04411654	AAV9	GBA1 PR001	(2)	Treated under compassionate use No procedure-related complications, well-tolerated
MPSI	RegenxBio	Phase 1/2 NCT03580083	AAV9	IDUA RGX-111	1	Well-tolerated and no severe AEs³
MPSII	RegenxBio	Phase 1/2 NCT03566043	AAV9	IDS RGX-121	3	Well-tolerated and no severe AEs³
FTD	Prevail Tx / Lilly	Phase 1/2 NCT04408625	AAV9	GRN PR006	1	Dec 2020
GM1 gangliosidosis	PassageBio	Phase 1/2 NCT04713475	AAVhu68	GLB1 PBGM01		Recruiting
Alzheimer's disease	LexeoTx	Phase 1/2 NCT03634007	AAVrh10	APOE2 LX1001	3	C1/C2 injection with CT
FTD	PassageBio	Phase 1/2 NCT04747431	AAV1	GRN PBFT02		Not yet recruiting
Krabbe	PassageBio	Phase 1/2 NCT04771416	AAVhu68	GALC PBKR03		Not yet recruiting

ICM RISKS: ICM procedure risks are all the standard risks associated with a procedure: Bleeding, infection, CSF leak, spinal headache (~5-10%), meningitis, damage to brainstem/cerebellum

1. T. Flotte presentation …
2. Zsuli et al. Poster at …
3. RegenxBio media release …

Peripheral leak/transduction in ICM

{Hauricot, 2013 #1613}

dog

Vector biodistribution following i.c. delivery of AAV9-GFP vectors to dogs

	Slow		Fast
	Dog 1	Dog 2	Dog 3	Dog 4
CNS
Rhinencephalon	1.82-3.4	1.62-5.86	15.36	1.72-4.2
Dorsal frontal cortex	5.85-6.58	2.36-3.34	2.20-3.05	5.4-6.2
Medial frontal cortex	3.82	1.67	1.49	1.24
Dorsal parietal cortex	1.07	0.03	1.68	1.93
Lateral parietal cortex	3.07	6.93	0.6	6.2
Temporal cortex	2.14	2.6	0.43	3.26
Piriform lobe	16.43	3.98	3.98	11
Hippocampus	0.82	1.49	3.75	0.86
Pons	3.25	0.31	0.1	3.37
Cerebellum	0.27-0.4	0.32-0.78	2-3.6	0.18-0.38
Medulla oblongata	0.3-1.17	1.22	NA	2.42-7.12
C3-C6	NA	0.34-0.51	10.39	7.22
Somatic tissues
Liver	4.72-6.61	1.75-1.52	4.13-7.77	2.73-1.54
Heart	0.09	0.05	0.24	0.01
Lung	0.22	0.12	0.48	0.04
Spleen	4.12	1.68	17.73	3.24
Pancreas	0	0	0.01	0
Intestine	0.07	0.01	0.03	0.02
Kidney	0.22	0.49	0.25	0.26
Skeletal muscle	0.23	0.13	0.25	0.04
Gonads	0.03	0.01	0.12	0.02
Cervical LN	2.9	1.82	3.69	0.01
Popliteal LN	NA	NA	0.42	0.56

Vector genome copy numbers were determined in different brain areas and in several somatic organs in dogs receiving slow or fast infusions of 2 × 10¹³ vg of AAV9-GFP vectors to the cisterna magna (Dogs 1-4). For those specimens for which 2 samples were available, both values are provided. NA, not available.

{nderer, 2018 #14}

dog

(Bar chart GC / Diploid Genome on log scale showing organ-specific transduction across multiple tissues, three coloured bars per tissue. Continues on next photo.)

Uncertain Spans

location	transcription	uncertainty
WORLDSympsium 2021 bullet	`대략, cortxt에 잘 분포함 (deep structure eg. striatum, thalamus, midbrain 시키)`	The trailing Korean shorthand `시키` reads as written; OCR returns the same string in both engines.
Hauricot 2013 #1613 row label	citation tag	OCR returns `Hauricot, 2013 #1613` but the surname may be `Haurigot` (Spanish researcher); preserved as printed in this capture.
Bottom row author tag	`{nderer, 2018 #14}`	The leading author surname is partly cropped by the table’s left edge; only `nderer` is visible (likely `Hinderer` 2018).

JS PD KB

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