Delivery of an anti‐transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons

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Abstract
Transthyretin (TTR) is a transport protein of retinol and thyroxine in serum andCSF, which is mainly secreted by liver and choroid plexus, and in smaller amounts in other cells throughout the body. The exact role ofTTRand its specific expression in Central Nervous System (CNS) remains understudied. We investigatedTTRexpression and metabolism inCNS, through the intranasal and intracerebroventricular delivery of a specific anti‐TTRNanobody to the brain, unveiling Nanobody pharmacokinetics to theCNS. InTTRdeficient mice, we observed that anti‐TTRNanobody was successfully distributed throughout all brain areas, and also reaching the spinal cord. In wild‐type mice, a similar distribution pattern was observed. However, in areas known to be rich inTTR, reduced levels of Nanobody were found, suggesting potential target‐mediated effects. Indeed, in wild‐type mice, the anti‐TTRNanobody was specifically internalized in a receptor‐mediated process, by neuronal‐like cells, which were identified as motor neurons. Whereas inKO TTRmice Nanobody was internalized by all cells, for late lysosomal degradation. Moreover, we demonstrate thatin vivomotor neurons also actively synthesizeTTR. Finally,in vitrocultured primary motor neurons were also found to synthesize and secreteTTRinto culture media. Thus, through a novel intranasalCNSdistribution study with an anti‐TTRNanobody, we disclose a new cell type capable of synthesizingTTR, which might be important for the understanding of the physiological role ofTTR, as well as in pathological conditions whereTTRlevels are altered inCSF, such as amyotrophic lateral sclerosis. image
Funding Information
  • Federación Española de Enfermedades Raras
  • Fundação para a Ciência e a Tecnologia (PEst‐C/SAU/LA0001/2011)

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