Gene therapy in early stages of Huntington’s disease may slow progression of symptoms

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PICTURE: Representative maps of cerebral blood volume in mouse brains of the genotypes and treatment groups indicated. The top row shows the raw images – the red regions of interest indicate the quantified view of the brain … After

Credit: Wenzhen Duan, MD, Ph.D.

In a new study in mice, researchers at Johns Hopkins Medicine report that using MRI scans to measure blood volume in the brain may serve as a non-invasive way to potentially track the progress of gene-editing therapies for early-stage Huntington’s disease, a neurodegenerative disease that attacks brain cells. Researchers say that identifying and treating the mutation known to cause Huntington’s disease with this type of gene therapy, before a patient starts showing symptoms, can slow the progression of the disease.

the results of the study were published on May 27 in the journal Brain.

“What is exciting about this study is the opportunity to identify a reliable biomarker that can track the potential success of genetic therapies before patients start showing symptoms,” says Wenzhen Duan, MD, Ph.D., Director of the Translational Neurobiology Laboratory and Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine. “Such a biomarker could facilitate the development of new treatments and help us determine the best time to start them.”

Huntington’s disease is a rare genetic disorder caused by a single defective gene, nicknamed “huntingtin”, on human chromosome 4. The gene is passed from parents to children – if one parent has the mutation, each child has a 50% chance to inherit it. Huntington’s disease is incurable and can lead to emotional disturbances, loss of intellectual capacity, and uncontrolled movement. Through genetic testing, people can find out if they have the disease long before symptoms appear, which usually happens in their 40s or 50s.

For the study, Duan and his team collaborated with colleagues from Kennedy Krieger Institute in Baltimore, Maryland, which developed a new method to more accurately measure blood volume in the brain using advanced functional MRI scans. With the scans, they can map the path of blood flow through small blood vessels called arterioles in the brains of mice designed to carry the mutation in the human huntingtin gene that reflects the early stages of Huntington’s disease in humans.

Duan notes that there are many known metabolic changes in the brains of people with Huntington’s disease, and that these changes initiate a cerebral blood volume response in the early stages of the disease. Blood volume is a key marker of oxygen delivery to brain cells, which in turn provides the energy for neurons to function. But with Huntington’s disease, the arteriolar blood volume in the brain is drastically reduced, causing neurons to deteriorate due to lack of oxygen as the disease progresses.

In a series of experiments, the researchers removed the mutation in the huntingtin gene in mice, using a gene-editing technology known as CRISPR – a genome-editing tool that enables the alteration of a DNA sequence to alter the function of genes. Then they used the MRI imaging technique and other tests to track brain function over time both in mice with the huntingtin mutation, in which they deleted the faulty genetic sequence, and in mice with the huntingtin mutation. a control group of mice in which the defective gene had not been modified.

The experiments evaluated abnormalities in the trajectory of arteriolar blood volumes in the brain of mice with the Huntington’s disease mutation at 3, 6 and 9 months (pre-symptom stage, onset of symptoms and post-symptom stage, respectively) . The researchers investigated whether deleting the mutant huntingtin gene in neurons could normalize altered arteriolar blood volumes in the pre-symptom stage, and whether reduced expression of the huntingtin gene in the pre-symptomatic stage could delay or even prevent it. development of symptoms.

“Overall, our data suggest that measuring cerebral arteriolar blood volume may be a promising non-invasive biomarker for testing new therapies in patients with Huntington’s disease who have not yet shown symptoms of the disease. “said Duan. “Introducing treatment at this early stage can have long-term benefits.”

When the researchers mapped the trajectory of cerebral blood volume and performed an assortment of brain and motor tests in the mice at 3 months of age, and compared the test to those in the control group, they found no significant difference, except in cerebral blood volumes. However, Huntington’s symptoms in mice carrying the huntingtin gene began at 6 months of age and gradually worsened at 9 months, suggesting that an alteration in cerebral blood volume occurs before motor symptoms and brain cell atrophy – typical features of the disease.

The changes in cerebral blood volume were also found to be similar to those seen in patients with Huntington’s disease before they began to show symptoms, which diminish with the onset of symptoms and as the disease progresses over time. time.

The researchers also analyzed the structure of arteriole blood vessels in the brains of mice carrying the mutant huntingtin gene at 3 and 9 months and found no difference in the number of vessel segments at the pre-symptomatic stage. However, they observed that the smaller blood vessels had increased density and reduced diameter, which may be a vascular response to compensate for impaired neuronal brain function. This could suggest, the researchers conclude, that an alteration in vascular structure leads to decreased arteriole blood volumes and possibly a compromised ability to compensate for symptom-stage loss.

Considering that the symptoms of Huntington’s disease depend not only on the loss of brain cells, but also on the deterioration of neurons, the researchers set out to determine whether suppressing the huntingtin gene at the pre-symptomatic stage in mice could. delay or even prevent the progression of the disease. To do this, the researchers introduced the altered huntingtin gene into the neurons of mice at the age of 2 months and evaluated the results at the age of 3 months (in the absence of atrophy or motor deficit ).

Remarkably, according to the researchers, the cerebral arteriolar blood volume in mice with the altered huntingtin gene was This suggests that the altered cerebral blood volume during the pre-symptomatic phase in mice is most likely due to neuronal changes in activity or metabolism.

“Our results demonstrate that significant changes in arteriolar cerebral blood volumes occur before neurons begin to degenerate and symptoms begin, which reinforces the idea that impaired cerebrovascular function is an early symptom of Huntington’s disease, ”says Duan. She explains that these changes also indicate that there is a pre-symptom therapeutic window in which to test interventions. Although no animal model replicates all of the symptoms of human Huntington’s disease, this research offers an alternative system to study functional changes in the pre-symptom stage, she says.

Further validation of these results in human clinical trials would facilitate the development of effective therapeutic interventions for patients with Huntington’s disease before they start to develop symptoms. “The goal is to delay or even completely prevent the onset of Huntington’s disease,” says Duan.

Along with Duan, other researchers who have contributed to the work are Hongshuai Liu, Chuangchuang Zhang, Jing Jin, Liam Cheng, Qian Wu, Zhiliang Wei, Peiying Liu and Christopher Ross of Johns Hopkins, and Jiadi Xu, Xinyuan Miao, Hanzhang Lu, Peter van Zijl and Jun Hua of the Kennedy Krieger Institute and Johns Hopkins.

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