Protein Therapeutics

Leach, Michael W.; Hammerman, Katherine

doi:10.1016/b978-0-12-821047-5.00024-5

Cited by 1 publication

(1 citation statement)

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“…The most common microscopic findings associated with IT-administered ASOs are granulated or vacuolated macrophages in the meninges (brain and spinal cord) and perivascular (Virchow-Robin) spaces (usually brain) as well as cytoplasmic vacuolation of neurons, both reflective of ASO accumulation, as well as mononuclear cell infiltrates in the meninges of the spinal cord and spinal nerve roots. 17,98 These findings are dose-and dose frequency-dependent in severity, may be reversible depending on the dose frequency, and thus are interpreted as non-adverse. Nerve fiber degeneration (minimal to occasionally mild) in the spinal cord and spinal nerve roots may accompany large leukocyte aggregates, especially in rodents, but this finding typically is uncommon and is more frequent near the IT injection site; therefore, it may be caused in part by trauma related to the injection procedure.…”

Section: Toxicologic Neuropathology Of Nucleic Acid Therapiesmentioning

confidence: 95%

Toxicologic Neuropathology of Novel Biotherapeutics

Bangari,

Lanigan,

Cramer

et al. 2023

Toxicol Pathol

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Biotherapeutic modalities such as cell therapies, gene therapies, nucleic acids, and proteins are increasingly investigated as disease-modifying treatments for severe and life-threatening neurodegenerative disorders. Such diverse bio-derived test articles are fraught with unique and often unpredictable biological consequences, while guidance regarding nonclinical experimental design, neuropathology evaluation, and interpretation is often limited. This paper summarizes key messages offered during a half-day continuing education course on toxicologic neuropathology of neuro-targeted biotherapeutics. Topics included fundamental neurobiology concepts, pharmacology, frequent toxicological findings, and their interpretation including adversity decisions. Covered biotherapeutic classes included cell therapies, gene editing and gene therapy vectors, nucleic acids, and proteins. If agents are administered directly into the central nervous system, initial screening using hematoxylin and eosin (H&E)-stained sections of currently recommended neural organs (brain [7 levels], spinal cord [3 levels], and sciatic nerve) may need to expand to include other components (e.g., more brain levels, ganglia, and/or additional nerves) and/or special neurohistological procedures to characterize possible neural effects (e.g., cell type-specific markers for reactive glial cells). Scientists who evaluate the safety of novel biologics will find this paper to be a practical reference for preclinical safety testing and risk assessment.

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Section: Toxicologic Neuropathology Of Nucleic Acid Therapiesmentioning

confidence: 95%