All it takes is a single genetic mutation to permanently alter one’s life, or even the course of one’s life — bringing about any number of recessive linked genetic disorders that can affect the entire body. For decades, people dreaded the possibility that they could develop Huntington’s disease later in life or that they could be a carrier for the gene — a disease that attacks the central nervous system. There are currently dozens of lysosomal storage diseases known to science that act in a similar way, where single mutations can create chemical barricades against producing the enzymes that cells need to perform basic functions. Often in these disorders, the brain is a target, resulting in various forms of intellectual disability.
Over the last two decades, gene therapy has been able to bring about miraculous new treatments for diseases, with CRISPR editing technology being hailed as one of the most significant breakthroughs in the history of medicine, giving us the ammunition we need to conquer most chromosomal disorders and end the centuries-old cycle of human suffering. The blood-brain barrier — a wall of cells made of the same material as your blood vessels, insulates the central nervous system and brain from the blood — is a buffer that keeps dangerous pathogens for invading the brain — and that’s why it’s very difficult for treatments where protein molecules — often the shell of a deactivated virus — deliver healthy genes to the body to effectively permeate it.
A study recently published in the journal Brain, however, has proposed a new possible approach. The research team, headed by John H. Wolfe, a researcher with the Children’s Hospital of Philadelphia, successfully tried a gene therapy platform on a model of a large animal brain and used it to correct a lysosomal genetic disorder.
“This is the first example of a large-brain mammal with a bona fide human genetic disease that has intellectual disability as part of the human syndrome where we’ve been able to correct the biochemistry and pathologic lesions in the whole brain,” says Wolfe.
Until now, gene therapy models that permeate the protective blood-brain barrier have been done successfully in treating rodents suffering from neurodegenerative diseases, but when it comes to working with larger mammals with more complex brains, the therapy has only shown partial corrections. Wolfe has long been convinced that certain vectors are capable of passing from the blood to the brain allowing treatments to repair serious neural damage. So far the treatment administered to his model has proved effective against a disease that attacks the spinal cord.
The brain used in the study by Wolfe and colleagues was closer in similarity to cats and humans than to rodents, and the condition they targeted was a lysosomal storage disease known as alpha-mannosidosis, which affects cats and occurs due to a mutation from copying the mannosidase gene. Untreated, it causes mental deterioration and hearing loss, while also weakening the skeletal system. The researchers used a similar vector that they tried on the blood-brain barriers of mice, spliced with a reporter gene (carrying the correct mutation) to treat the disorder in their model. Then, as a follow-up, Wolfe’s team distributed the same vector to normal house cats. Several weeks after the initial trials, they discovered that copies of the improved gene had been replicated throughout the cats’ brains — into the cerebral cortex, hippocampus and mid-brain.
In their last phase, the researchers administered their therapy to cats who suffered with alpha-mannosidosis, dividing them into groups who received either low or high doses of the vector with the right gene. The vector was injected into the carotid artery, sending it directly to the brain before it circulated throughout the body. Their onset of symptoms was delayed considerably compared to cats with the disorder who were given no treatment. The cats from the group given the highest injections also lived the longest.
“It’s a big advance,” says Wolfe. “Nobody has been able to treat the whole brain of a large-brained animal before. We’re hopeful that this will translate into clinical use in humans.” He is quick to point out, however, that we aren’t quite out of the woods yet — and his discovery should not suggest that a cure has been found.
At present, alpha-mannosidosis is capable of serious suffering in humans — first afflicting its victims in early childhood, and options for treating it are limited. While significant improvements had been made in the morbidity of this disease, Wolfe is hoping he can achieve more working with less of a dosage, and sees this as the beginning of a new therapy for the central nervous system, while causing as little harm as possible.
