Voyager Therapeutics : Discovery and Characterization of Novel Cross-Species BBB-Penetrant Capsids (ASGCT 2023)

Discovery and Characterization of Novel Cross-

Species BBB-Penetrant Capsids

Brett Hoffman, Tatiana Knox, Tyler Moyer, Ishan Shah, Shanan Emmanuel,

Mathieu Nonnenmacher

Disclosures

• Full-timeemployee at Voyager Therapeutics

© Voyager Therapeutics

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Delivery of Gene Therapies by Adeno-associated Virus (AAV)

• First AAV-mediated gene therapy approved in 2012
• • Glybera® (AAV1) - lipoprotein lipase deficiency
  • Luxturna ® (AAV2) - Leber congenital amaurosis
  • Zolgensma ® (AAV9) - spinal muscular atrophy
  • Hemgenix ® (AAV5) - hemophilia B
• Entry of systemically delivered AAV to the CNS is largely impeded by the blood-brain barrier (BBB).
• AAV9 is the most efficient natural serotype at crossing the BBB and transducing the CNS
• Requires a high viral load to achieve limited CNS transduction

© Voyager Therapeutics

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Directed Evolution of AAV for CNS Delivery - TRACER™

TRACER™ - Tropism Redirection of AAV by Cell-type-specific Expression of RNA

VR-VIII

7-mer Insert

Nonnenmacher et al. Mol. Ther. Methods Clin. Dev. 2020 © Voyager Therapeutics

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Directed Evolution of AAV for CNS Delivery - TRACER™

TRACER™ - Tropism Redirection of AAV by Cell-type-specific Expression of RNA

AAV9

9P31

385-fold Increased EGFP Expression vs AAV9

IV dosing, 4e11 VG, scAAV,

anti-GFP staining

9P801 CNS Transduction in Adult Macaques

	100	9P801 TRACER AAV9 Derivative
	10	1,000 - 10,000x
TBP)	1
vs
(Fold	0.1
	Conventional AAV9
mRNA	0.01
	0.001
	0.0001

	CortexCortexCortex		Cortex	CortexCortexCortex		Cortex
			Thalamus				Thalamus
	Motor	Putamen			Motor	Putamen
	Cerebellar			Cerebellar
Sensory		Sensory
Frontal				Frontal

IV dosing, 2e13 VG/kg, ssAAV

AAV9 9P801

2.0E13 2.0E13

Dentate

Nucleus

Hippocampus

Substantia

Nigra

Thalamus

IHC detection of transgene protein

© Voyager Therapeutics

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