Effectiveness of Gene Therapy Delivery to the Brain Varies by Species

Edith Pfister, Ph.D. - September 19, 2019

In reviewing a recent Molecular Therapy article, Edith Pfister, Ph.D., associate editor of ASGCT's newsletter The Vector, outlines patterns of virus CNS transduction efficiency in non-human primates in comparison with mice.

<p>Dose escalation of AAV-PHP.B in the mouse brain following intravenous and intra-arterial delivery</p>

Disorders of the central nervous system have long defied the efforts of scientists to develop effective treatments. This is due both to the complex nature of these diseases and to the particular problems associated with reaching the affected structures.

Neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease affect structures deep within the brain. Treatments delivered systemically must be able to penetrate the blood brain barrier and be able to penetrate deep into the brain parenchyma. New methods of capsid library generation and screening led to much hope that AAVs would be able to overcome these barriers, and even be able to be tailored to deliver their cargo with precision to the areas of need.

Indeed, using an evolutionary approach, Deverman et al. generated a novel AAV9 based capsid AAV-PHP.B which shows broad brain distribution following systemic delivery1. Some consternation followed when it seemed that this capsid exhibited the desirable behavior only in one strain of mice, or only in some strains of mice, or only in mice (you’d be forgiven for not knowing which, as it was a fast moving target) which initially left the future clinical relevance of this vector unknown.

This uncertainty has recently been cleared with the publication, by multiple groups, of an isoform of the Ly6a gene which is responsible for the blood brain barrier penetrating properties of AAV-PHP.B2,3. Liguore et al. have just provided an additional layer of complexity to this question. They show that in NHPs, unlike in mice, the route of delivery matters. In C57/BL6 mice, delivery to the jugular vein, carotid vein, lateral ventricle and cisterna magna, all produce roughly the same distribution (with the exception of better delivery to the striatum in the group injected in the lateral ventrical).

In contrast, in Rhesus macaque, delivery into the cisterna magna appeared superior to delivery to the carotid artery. It seems likely that multiple factors are in play here: differences in the natural tropism of the capsid in mice vs. Rhesus macaque may interact with differences in brain size, body size, and CSF flow to produce dramatic differences in vector biodistribution.

Happily, for patients who are waiting for novel methods to treat the diseases affecting deep brain structures, the research is continuing to progress rapidly.

1.           Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016).

2.           Hordeaux, J. et al. The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier. Mol. Ther. 27, 912–921 (2019).

3.           Huang, Qin, et al. Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP. B capsids. bioRxiv (2019): 538421.

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