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

Pharmaceutics, 2022 · DOI: https://doi.org/10.3390/pharmaceutics14010200 · Published: January 15, 2022

Simple Explanation

This study investigates the safety and tolerability of a novel antisense oligonucleotide (NVP-13) in cynomolgus monkeys. NVP-13 targets TGFBR2, a gene involved in neurodegenerative diseases. The drug was administered directly into the spinal fluid (intrathecally) over 13 weeks to assess potential toxic effects on the nervous system and other organs. The doses used were 1, 2, and 4 mg per animal. The study found that NVP-13 was well-tolerated with no significant adverse effects observed in various physiological and clinical chemistry parameters, suggesting it's a promising candidate for treating neurodegenerative disorders in humans.

Study Duration

13 weeks

Participants

40 cynomolgus monkeys (Macaca fascicularis), male and female

Evidence Level

Not specified

Key Findings

1
NVP-13 demonstrated excellent local and systemic tolerability in cynomolgus monkeys following repeated intrathecal injections.
2
No adverse events were observed in physiological, hematological, clinical chemistry, and microscopic findings.
3
The no observed adverse effect level (NOAEL) was determined to be at least 4 mg/animal NVP-13 under the conditions of this study.

Research Summary

The study assessed the safety and tolerability of NVP-13, an antisense oligonucleotide targeting TGFBR2, following repeated intrathecal administration in cynomolgus monkeys. Results showed that NVP-13 was well-tolerated with no significant adverse effects on physiological, hematological, or clinical chemistry parameters. The no observed adverse effect level (NOAEL) was determined to be at least 4 mg/animal, indicating that NVP-13 is a promising drug candidate for treating neurodegenerative disorders.

Practical Implications

Potential Therapeutic for ALS

NVP-13 could be a potential drug candidate for treating ALS and other neurodegenerative disorders by targeting the TGFβ signaling pathway.

Safe Intrathecal Administration

The study demonstrates the safety of intrathecal administration of NVP-13 in non-human primates, paving the way for clinical trials.

Reconditioning Neurogenic Niche

NVP-13 shows promise in reconditioning the neurogenic niche of adult non-human primates, potentially promoting neuroregeneration.

Study Limitations

1
The study was conducted in healthy animals and not in disease model animals, limiting the assessment of individual animal’s TGFβ signaling status.
2
Transient absence of food and patellar reflexes were observed, indicating potential neurological effects that require further investigation.
3
Mononuclear cell infiltrates were observed in the central nervous system, suggesting a pro-inflammatory response that needs to be carefully monitored in future clinical trials.

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