Gene editing: Is it the future for the treatment of neurodegenerative diseases?

From designer babies to cancer therapy, gene editing is a controversial topic. However, human genetic modification is now a viable technology with a huge number of potential uses, including for the treatment of neurodegenerative diseases.

Characterised by memory loss and progressive cognitive decline, Alzheimer’s disease (AD) affects between 10–30% of people over the age of 65, making it the most common form of dementia. Although there are drugs that can alleviate some of the symptoms in the early stages of AD, there are currently no pharmacological therapies that cure the disease or increase life expectancy after diagnosis. Although the exact pathogenic processes in AD are still uncertain, the accumulation of amyloid-beta (Aβ) is very important in the early aberrations that cause AD.

Nonetheless, a recent paper published in Nature Neuroscience has showed in vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease.

This paper used CRISPR-Cas9, a technology based on proteins found in the bacterial immune system, to edit genes by cutting DNA at specific points in its sequence. This allows researchers to create very specific changes to genes, for example removing or inserting section of DNA, or inducing mutations to alter gene function. In this study, CRISPR-Cas9 nanocomplexes are used to mutate the gene for beta-secretase (Bace1), an enzyme involved in the production of Aβ. The authors first showed that they could specifically reduce Bace1 levels and hence Aβ production in adult neurons in vitro.

Subsequent experiments then investigated the effect of injecting these complexes into small regions of the hippocampus (the brain structure associated with memory) in mouse models of AD, which contain mutations that in humans cause familial or early-onset AD. These mice show many of the pathological hallmarks of AD from as early as 4 months of age, including the aggregation of Aβ into plaques and poor spatial memory in behavioural testing. Injection of the nanocomplexes into the brains of these mice significantly improved the performance in several cognitive behavioural tests compared to controls, including spatial memory. For the first time, this showed that gene editing can be used in adult brains, making it an important proof-of-principle study.

Although this finding gives us much hope that this technology could be translated into humans, caution is also needed in interpreting its results. For example, the mice used had as many as 5 AD-associated mutations, which never occurs in humans. Moreover, these mice show cognitive deficits very soon after the development of Aβ pathology, but in humans, clinical symptoms don’t appear for several decades after the initial pathology starts. Together, these caveats question whether these mice are good models of the disease. They also only test the effects of this treatment 12 weeks after injection, so it is still unknown whether their beneficial effects will persist long-term. Nevertheless, with further experimental validation, this could be a major step forward in the treatment of AD.

However, this isn’t the first time CRISPR-Cas9 has been used in neurodegenerative disease. Another recent study has shown that epigenetic regulation using CRISPR-Cas9 could rescue cellular characteristics of Parkinson’s Disease: “Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD”. The effects of Parkinson’s Disease are more focal than broad network dysfunction seen in AD, so more specific benefits may be possible in this disease.

While this technology is still in its infancy and the experiments are far from conclusive, these exciting findings suggest gene editing could be a real opportunity for the future treatment of neurodegenerative conditions. Nonetheless, the major barrier to the use of genome editing in the context of neurodegenerative diseases will be the associated ethical issues, which will need to be fully considered before this treatment can be regularly used in patients.

DPhil Student in Neuroscience at the University of Oxford 🔬 Science 🧠 Neuroscience 🎓 University Life