Expert guidance on classifying adverse vs. nonadverse nerve fiber degeneration in intrathecal oligonucleotide nonclinical toxicity studies.
Authors: Lisa D. Berman-Booty, Ingrid D. Pardo, Brad Bolon, Kuldeep Singh, James P. Morrison, Shelley Patrick, Sarah Cramer, and Jessica L. Grieves

Explore evidence-based guidance for distinguishing adverse from nonadverse nerve fiber degeneration in nonclinical toxicity studies of intrathecally administered oligonucleotide therapeutics.

Determining adversity and the no observed adverse effect level (NOAEL) in nonclinical toxicity studies is an important judgment a pathologist makes during pharmaceutical development. For oligonucleotide (ON) therapeutics delivered via the intrathecal (IT) route, that judgment involves additional complexity. IT delivery itself can produce nerve fiber degeneration (NFD), which means findings must be carefully contextualized before any conclusion about drug-related risk can be drawn.

A new opinion article published in Toxicologic Pathology shares guidelines for interpreting adversity of nerve fiber degeneration (NFD) in the context of intrathecally delivered oligonucleotides. StageBio, as part of a team of experienced toxicologic pathologists, offer practical guidance for interpreting adversity of NFD in nonclinical studies of antisense oligonucleotides and short interfering RNAs administered intrathecally.

Key topics covered in the paper include how to differentiate IT delivery procedure-related NFD from ON-related effects or ON-related exacerbation of procedure-related findings, how to assess NFD in the brain, spinal cord, spinal nerve roots, ganglia, and peripheral nerves, and the role of functional and behavioral data, neuronal necrosis, and inflammatory response in adversity determinations.

Setting the threshold: When is nerve fiber degeneration actually adverse?

The central question in evaluating IT ON studies is not simply whether NFD is present, but whether it represents a biologically meaningful harm. A clear framework for making that distinction can help sponsors avoid misclassifying findings in either direction, which could lead to artificially conservative NOAELs or underestimated risk.

This opinion article proposes a position: nonextensive, regionally restricted, minimal or mild NFD that occurs in the absence of functional or behavioral deficits, neuronal necrosis, or substantial neural inflammation may be interpreted as nonadverse. That interpretation, applied consistently and with rigorous documentation, can support NOAEL determinations and regulatory submissions.

For sponsors advancing ON therapeutics through nonclinical development, this kind of nuanced pathology expertise plays an important role in producing data that will hold up to regulatory scrutiny.

Access the full opinion article published in Toxicologic Pathology

Download the paper here.