Gene therapy targeting the blood-brain barrier

Available online 12 April 2024

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Endothelial cells are the building blocks of vessels in the central nervous system (CNS) and form the blood-brain barrier (BBB). An intact BBB limits permeation of large hydrophilic molecules into the CNS. Thus, the healthy BBB is a major obstacle for the treatment of CNS disorders with antibodies, recombinant proteins or viral vectors. Several strategies have been devised to overcome the barrier. A key principle often consists in attaching the therapeutic compound to a ligand of receptors expressed on the BBB, for example, the transferrin receptor (TfR). The fusion molecule will bind to TfR on the luminal side of brain endothelial cells, pass the endothelial layer by transcytosis and be delivered to the brain parenchyma. However, attempts to endow therapeutic compounds with the ability to cross the BBB can be difficult to implement. An alternative and possibly more straight-forward approach is to produce therapeutic proteins in the endothelial cells that form the barrier. These cells are accessible from blood circulation and have a large interface with the brain parenchyma. They may be an ideal production site for therapeutic protein and afford direct supply to the CNS.

Section snippetsNon-viral vectors targeting the blood-brain barrier

To target the BBB, non-viral vectors are of considerable interest because they have low genotoxicity and immunogenicity compared to viral vectors (Pack et al., 2005, Thomas and Klibanov, 2003). Non-viral vectors can overcome limitations caused by biocompatibility, packaging capacity and manufacturing (Yin et al., 2014). Various non-viral vectors, consisting of specific polymers, receptor ligands, and liposomes among others, have been assessed for their ability to deliver genes to the BBB.

Adeno-associated virus

Accidently being discovered in the mid-1960s by electron microscopy as contaminant in laboratory simian adenovirus (SV15) preparations, the AAV was identified shortly after as “defective viral particle” which can only be replicated in the presence of adenovirus (Atchison, Casto, & Hammon, 1965). With a diameter of about 25 nm (Bowles, Rabinowitz, & Samulski, 2006) this non-enveloped single stranded DNA virus belongs to the smallest known viruses (Louten, 2016). The AAV capsid is composed of

Strategies to improve the tropism of adeno-associated viral vectors for the blood-brain barrier

Despite the fact that many natural AAV variants primarily target hepatocytes upon systemic administration, many of them also possess the ability to transduce vascular endothelial cells (Hennigs et al., 2021). Among the natural AAV serotypes, AAV9 and AAVRh.10 were the first to attract attention in the field of neuroscience due to their ability to transduce parenchymal brain cells upon systemic administration (Manfredsson et al., 2009, Tanguy et al., 2015). Following intravenous injection, AAV

Therapeutic use of gene therapy targeting the blood-brain barrier

The strategy of treating diseases of the CNS by targeting the BBB has been tested in preclinical studies and no clinical trials have been performed so far. Animal studies provide evidence that diverse diseases can be treated with this approach. So far, no major side effects were observed in mice. Preclinical data suggest two fields of application, which we will discussed below.

Conclusions and perspectives

Gene therapy of CNS and neurovascular disorders holds great potential. rAAVs appear most promising among different gene delivery strategies targeting the BBB. Since they have obvious potential at least in monogenetic diseases affecting the BBB, the use of AAV vectors targeting brain endothelial cells needs to be tested in polygenetic or non-genetic disorders of the barrier. They may also prove to be successful for continuous delivery of proteins to the CNS parenchyma. At least in mice, AAVs

References (122)F.P. Manfredsson et al.AAV9: A potential blood-brain barrier buster