Gene therapy – a global uprising

Gene therapy – a phrase with big impact, and significant current relevance. It is used to treat genetic diseases by replacing or modifying the faulty genes that cause them, and, if successfully harnessed, could provide a powerful method of treatment against currently incurable illnesses.

In this review I will outline the results of a recent paper by Agustin-Pavon et al, which contribute towards a potential gene therapy treatment for Huntington’s disease.

Huntington’s disease is monogenic; that is, caused by one gene- huntingtin (HTT). It is also genetically dominant, offspring of carriers with the mutant HTT are 50% at risk of carrying the defective gene too. Mutant HTT contains an expanding DNA CAG region that codes for excess polyCAG transcripts and expanded glutamine proteins, which are cytotoxic and damage neurons in the brain. Huntington’s develops in 1 in 10,000 people in the UK, and currently is incurable.

How does gene therapy fit in?

The recent uprising in the powerhouse of genetic modification techniques has CRISPR-Cas9 as its forerunner. However, there are other molecules by which target genes can be selectively silenced and modified, one class of which being Zinc Finger Proteins (ZFP). In an attempt to reduce the progression of Huntington’s disease in mice, researchers created a unique zinc-finger protein – ZF-KOX1 – which has successfully managed to prevent the neurological effects of Huntington’s disease for up to three weeks post-injection.

But it’s not as simple as that…the trouble with foreign proteins 

Foreign proteins can stimulate excessive immune inflammatory responses if they are recognised by a host’s immune system, regardless of whether they are helpful or harmful to the host. To avoid extensive neuronal damage when injecting artificially made ZFP, researchers host-matched the ZF-KOX1 to match the unique immune system of the mice, so it would not be recognised as foreign. The ZF-KOX1 was expressed in a rAAV vector, alongside a pNSE promoter for prolonged expression.

In mice, the ZF-KOX1 can bind to the expanded DNA-CAG repeats in the mutant HTT gene, and does not affect any other CAG-containing genes. This binding represses genetic expression, so no polyCAG transcripts and polyQ peptides are produced. In the mice, ZF-KOX1 prevented neurological symptoms of Huntington’s for up to three weeks – a result which was potentially achieved by the promoter extending the longevity of the construct in the cells. Tests showed up to 77% repression of mutant HTT transcripts over these three weeks, and 23% repressed after 24 weeks.

Why is this important? 

Potentially, this ZFP could be developed in a treatment to prevent progression of Huntington’s disease. However, we must first be definite that this is not a cure, and not a prevention – and not yet even close to being a widely-available treatment. As discussed in my article on Alzheimers, we cannot jump the gun too soon, and claim that this is the ultimate treatment for ending Huntington’s disease. Developing a human-specific treatment will take a long time, as this construct currently only represses progression up to 3 weeks, and we do not know if it will even be replicable in humans. The brain is also a notoriously difficult area to target treatment to- it is immunocompromised (aka is not part of the general immune system, and cannot be reached by antibodies or T cells), but can still stimulate a strong inflammatory response when infected by viral vector. However, this is still a promising step forward, and represents a distinct success for gene therapy treatments against currently incurable diseases.


The paper: Agustin-Pavon et al. Deimmunisation for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice.   2016. Molecular Neurodegeneration.

Words in pink can be found in the glossary

Image: Wikimedia commons


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