Findings suggest new route to delivery of CRISPR gene therapy in animal Models

Scientists have identified a new route to deliver CRISPR gene therapy in animal models of Huntingtons disease. By modifying the proteins that are expressed by liver cells the researchers were able to increase their survival rate by 48 and restore damaged brain tissue back to a normal state. The study has been published in the journal Cell Reports.

About 30-40 of patients suffering from Huntingtons disease have a defective form of the protein. These patients are unable to not die from the disease.

One of the major challenges of treating people with long-term ALS-related motor neuron atrophic injury (NMND) is that their nervous systems start to die as well even before they will show any symptoms. This leads to a slow progressive progressive deterioration in their quality of life.

Neuronal regeneration is required for normal brain functioning and the restoration of deep structures like the brain and eye due to devastating loss of sight and cognitive function.

The currently accepted approach to treat NMND is to induce a temporary form of chronic ALS-like inflammation mediated by the neuroprotective protein called neurofilament light chain (NfL) neurotrophic factor (NfL) which facilitate regeneration and restoration of this peripheral nervous system.

However the activation of NfL by neurofilament light chain (NfL neurotrophic factor) has been unsuccessful in clinical trials leading to the belief that alkaline pH could be a promising alternative for the treatment of neuroinflammation. Therefore it has been hypothesized that a neutral pH environment could provide a promising non-invasive alternative.

In this study researchers from Trinity College Dublin in collaboration with Nottingham Trent University monitored the stability of NfL in liver cells (livers that export some of their internal cellular material and are known to be sensitive to pH changes). The researchers found that NfL level in the liver was decreased by 10-12 upon treatment with a pH environment and by 79-88 upon treatment with an alkaline pH environment.

According to the researchers these findings suggest a novel route to delivery of CRISPR gene therapy in animal models of Huntingtons disease. Untreated the treatment allowed the mice to recover from NfL neurotrophic injury and experienced memory deficit after about 40 days in a confined environment.

Our study has identified a new possible non-invasive treatment for NMND that includes modification of the levels of NfL released by livers. By the high levels of NfL in the liver after treatment we are apparently able to restore the ability of the transplanted neurones to produce their normal blood-glucose as well as motor-signal-specific signals on the transplanted neurons.

Lucy Robinson from Trinity Ireland.

NfL neurotrophic factor was already known to also protect the health of other peripheral organs in a mouse model of chronic underlying liver failure. This study using mice suggests that modulating NfL levels may also offer a non-invasive means to improve the health of both neurones and visceral nerves.

The next stage of this trial will involve a clinical trial in patients with Huntingtons disease to determine how NfL in the liver can be modulated to improve motor symptoms. Trials will also focus on the clinical management of patients with active relapsing-remitting liver failure.