The recent report by the Cleveland/Isis groups represents a remarkable breakthrough, with potential for therapeutic application for humans. The long-lasting beneficial effects of intrathecal delivery of huntingtin (Htt) antisense oligonucleotides (ASOs) on HD mouse model phenotypes are unexpected and dramatic. While they offer the hope for rapid translation into human therapeutics, a number of issues must be considered.

The first relates to the time course of therapeutic effects. This may actually be the least problematic in practice, since if necessary, ASOs could be delivered to human HD patients frequently or even continuously by the intrathecal route.

The second relates to the effects of depleting normal huntingtin from neurons. The data in the systems studied suggest that substantial reductions do not have deleterious effects, but the possibility of neurotoxicity of reduction of normal Htt in humans will need to be addressed. The transgenic models studied in this paper have two copies of the normal allele, while humans with HD have only one normal copy plus one...  Read more

The recent report by the Cleveland/Isis groups represents a remarkable breakthrough, with potential for therapeutic application for humans. The long-lasting beneficial effects of intrathecal delivery of huntingtin (Htt) antisense oligonucleotides (ASOs) on HD mouse model phenotypes are unexpected and dramatic. While they offer the hope for rapid translation into human therapeutics, a number of issues must be considered.

The first relates to the time course of therapeutic effects. This may actually be the least problematic in practice, since if necessary, ASOs could be delivered to human HD patients frequently or even continuously by the intrathecal route.

The second relates to the effects of depleting normal huntingtin from neurons. The data in the systems studied suggest that substantial reductions do not have deleterious effects, but the possibility of neurotoxicity of reduction of normal Htt in humans will need to be addressed. The transgenic models studied in this paper have two copies of the normal allele, while humans with HD have only one normal copy plus one mutant copy.

The most important questions will relate to the anatomical areas to which ASOs can be delivered. The flow of CSF will mean that intrathecal delivery may restrict the ASOs primarily to the cerebral cortex, and perhaps especially to superficial layers. Humans are 15 times as large as the monkeys studied, and the monkey data showed clear uptake of the ASOs for only a few mm into the cerebral cortex.

As mentioned in the paper, the grey matter of cortex does show atrophy in human HD. However, both the PREDICT-HD and TRACK-HD studies suggest that this occurs relatively late, and that the subcortical white matter shows even greater atrophy, which begins earlier in the disease process. The striatum, of course, is affected earliest and most selectively. Major unanswered questions about HD pathogenesis involve how much neurodegeneration is cell autonomous, and how much is dependent on brain circuitry—and if the latter, how primary is the cortical grey matter. If cortical grey matter is not primary, or if the ASOs do not sufficiently penetrate to the deep cortical layers which project to the striatum, then intrathecal delivery may not be sufficient for human HD, unless it is possible to increase the concentration in order to extend penetration further.

If intrathecal delivery alone does not provide sufficient penetration in humans, it is conceivable that intrathecal delivery of ASOs could be combined with intraventricular delivery, or with intraparenchymal delivery of antisense RNAi reagents, perhaps using viral vectors.

But, despite these questions, it should be emphasized what an important step forward this paper represents. It also demonstrates the value of the discovery of the mutant HD gene and its abnormal protein product, and the use of modern molecular biology techniques for therapeutics. And if this antisense strategy works in humans, it will provide a key proof of principle for using the Htt protein itself as a target for HD therapeutics. Future strategies may involve using small molecules to target the Htt RNA, or to target key Htt post-translational modifications, and thus, even without the need for delivery directly to the CNS, to derive the benefit from the anti-Htt approach. Furthermore, all these principles can be applied to other neurodegenerative diseases—including Alzheimer’s disease.

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