Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

URN to cite this document:

urn:nbn:de:bvb:355-epub-519789 Copy

DOI to cite this document:

10.5283/epub.51978 Copy

Peters, Sebastian Thomas ; Wirkert, Eva ; Kuespert, Sabrina ; Heydn, Rosmarie ; Johannesen, Siw Wollebæk ; Friedrich, Anita ; Mailänder, Susanne ; Korte, Sven ; Mecklenburg, Lars ; Aigner, Ludwig ; Bruun, Tim-Henrik ; Bogdahn, Ulrich

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Date of publication of this fulltext: 28 Mar 2022 12:57

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Details

Item type:	Article
Open Access Type:	Gold (with APC)
Höhe Gebühr (aus OpenAPC):	2124.61
Institution der Zahlung:	Regensburg U
Journal or Publication Title:	Pharmaceutics
Publisher:	MDPI
Place of Publication:	BASEL
Volume:	14
Number of Issue or Book Chapter:	1
Page Range:	p. 200
Date:	15 January 2022
Institutions:	Medicine > Lehrstuhl für Neurologie
Identification Number:	Value Type 10.3390/pharmaceutics14010200 DOI
Keywords:	AMYOTROPHIC-LATERAL-SCLEROSIS; BETA; INHIBITION; NUSINERSEN; RILUZOLE; INJURY; AGENT; TGF beta-signaling; neurogenesis; neurodegeneration; amyotrophic lateral sclerosis; GLP-ToxStudy; antisense oligonucleotide therapy; LNA
Dewey Decimal Classification:	600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	51978

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Abstract

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGF beta system to represent a ...

Abstract

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGF beta system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide "NVP-13 ", targeting TGFBR2, effectively reduced its expression and lowered TGF beta signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

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Metadata last modified: 29 Nov 2022 15:59

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