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 zum Zitieren dieses Dokuments:

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

DOI zum Zitieren dieses Dokuments:

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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Lizenz: Creative Commons Namensnennung 4.0 International PDF - Veröffentlichte Version (3MB)

Veröffentlichungsdatum dieses Volltextes: 28 Mrz 2022 12:57

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Alternative Links zum Volltext:DOIVerlagVerlag

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Details

Dokumentenart:	Artikel
Open Access Art:	Gold (mit APC - bezahlt UR)
Titel eines Journals oder einer Zeitschrift:	Pharmaceutics
Verlag:	MDPI
Ort der Veröffentlichung:	BASEL
Band:	14
Nummer des Zeitschriftenheftes oder des Kapitels:	1
Seitenbereich:	S. 200
Datum:	15 Januar 2022
Institutionen:	Medizin > Lehrstuhl für Neurologie
Projekte:	German Federal Ministry of Education and Research (BMBF Project GO-Bio: 031A386, MND-Net), German Ministry of Economics and Energy (BMWI, ZIM-funding: KF2525608MD3), Bavarian Ministry of Economics, Energy and Infrastructure (PTJ, BayBIO: BIO-1506-0002)
Identifikationsnummer:	Wert Typ 10.3390/pharmaceutics14010200 DOI
Stichwörter / 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-Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin
Status:	Veröffentlicht
Begutachtet:	Ja, diese Version wurde begutachtet
An der Universität Regensburg entstanden:	Ja
Dokumenten-ID:	51978

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Zusammenfassung

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 ...

Zusammenfassung

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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