In each of the 50 families from the Netherlands, UK, USA and China, there was a child paralyzed by a mutation in the Cntnap1 (Contactin-Associated Protein 1) gene. These children are unable to move. Their families feed them, change their diapers, and have someone monitor them around the clock. Human CNTNAP1 mutations are associated with myelinating neuropathy type 3 (hypomyelinating neuropathy-3), which causes severe neurological deficits.
In a new study, Manzoor Bhat, MD, PhD, of the University of Texas Health Science Center at San Antonio, and his team made discoveries that hold promise for a gene therapy for these severely affected children. The findings were published online Oct. 19, 2023, in Cell Reports under the title "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological disorders". genetic restoration of murine neurological deficits".
Bhat said, "We obtained genetic information from these families and constructed transgenic mouse models that recapitulate human mutations and human diseases. Our mice exhibit the same phenotypes or weaknesses as these children." Bhat is a leader in neuron-glial biology research, and his lab discovered the mouse Cntnap1 gene in 2001.
A method of rescue
A transgenic animal is one in which a foreign gene has been introduced into the genome. the transgenic mice developed in Bhat's lab have both a normal copy of the Cntnap1 gene and a mutant copy reflecting the mutation observed in these children. says Bhat, "We can control when the normal gene is turned on. It turns out that we can use the normal gene to rescue these mice from their neurological deficits."
In a series of experiments, these authors turned on the normal Cntnap1 gene at birth, five days after birth, two weeks after birth, one month after birth, and three months after birth in the mice. The earlier they turned on the normal Cntnap1 gene, the faster these mice got better and the more complete the rescue was.
The longer we waited, the worse these mice got," Bhat said. This is because the Cntnap1 gene produces a protein that drives the conduction of nerve impulses. If we wait a month or two, then the nerve function is already weak, the muscles become weak, and the mice can't maintain motor coordination."
Image from Cell Reports, 2023, doi:10.1016/j.celrep.2023.113274.
These mice were placed on a beam to measure their movement. After the normal copy of the Cntnap1 gene was turned on, over time they began to pass the beam with ease. This is because the normal Cntnap1 gene produces proteins that improve nerve signaling.
The road to gene therapy
The next phase of this new research is to inject Cntnap1 mutant mice with a virus that makes the Cntnap1 protein. If preclinical studies show promising results, the next step would be gene therapy in children.
The mouse model we constructed is the first mouse model of the disease and the first rescue of the disease," Bhat says. We are now preparing for future gene therapy."
