Search

Antibody therapies for Alzheimer's Disease (AD) hold promise but have been limited by the inability of these proteins to migrate efficiently across the blood brain barrier (BBB). Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies' own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-β have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. While expression of canonical IgG in the brain led to signs of neurotoxicity, this modified Ab was efficiently secreted from neuronal cells and retained target specificity. Steady state levels in the brain exceeded peak levels obtained by intravenous injection of IgG. AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive β-amyloid plaque accumulation. These findings suggest that CNS gene delivery of a silent anti-Aβ scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer's disease., Competing Interests: All authors are present or past employees of Sanofi, which provided funding for this work. this support does not alter our adherence to PLOS ONE policies on sharing data and materials. A patent application has been filed by Sanofi on gene delivery of modified antibodies for the treatment of CNS indications.

Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme-replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol β epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD.

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. [ABSTRACT FROM AUTHOR]

The increasing specificity of novel druggable targets coupled with the complexity of emerging therapeutic modalities for treating human diseases has created a growing need for nonhuman primates (NHPs) as models for translational drug discovery and nonclinical safety assessment. In particular, NHPs are critical for investigating potential unexpected/undesired on-target and off-target liabilities associated with administration of candidate biotherapeutics (nucleic acids, proteins, viral gene therapy vectors, etc.) to treat nervous system disorders. Nervous system findings unique to or overrepresented in NHPs administered biomolecule-based ("biologic") test articles include mononuclear cell infiltration in most neural tissues for all biomolecule classes as well as neuronal necrosis with glial cell proliferation in sensory ganglia for certain viral vectors. Such test article-related findings in NHPs often must be differentiated from procedural effects (e.g., local parenchymal or meningeal reactions associated with an injection site or implanted catheter to administer a test article directly into the central nervous system) or spontaneous background findings (e.g., neuronal autophagy in sensory ganglia). [ABSTRACT FROM AUTHOR]