Intranasal delivery of human NGF eases Rett symptoms in mice
Noninvasive treatment helped improve cognitive, motor function in study
Into-the-nose delivery of a solution containing clinical-grade human nerve growth factor (NGF) improved cognitive and motor function in a mouse model of Rett syndrome, including in male mice with more severe and rapidly advancing symptoms, a study has found.
This could be “a non-invasive and effective route of administration for the treatment of Rett syndrome,” a team of researchers in Italy wrote in the study “Clinical-grade intranasal NGF fuels neurological and metabolic functions of Mecp2-deficient mice,” which was published in Brain.
Rett syndrome is most often caused by mutations in MECP2, a gene that provides the instructions needed to produce a protein that is key for the brain to develop normally. Such mutations interfere with how neurons function, thereby causing symptoms.
NGF thought to be present at low levels in brains of people with Rett
Like other neurotrophins, a family of proteins that can signal nerve cells to develop and survive, NGF is thought to be present at low levels in the brain of people with Rett syndrome. In an earlier study, intranasal (into-the-nose) delivery of NGF eased behavioral symptoms in a mouse model of the disease.
In the new study, the researchers tested a clinical-grade formulation of recombinant (lab-made) human NGF for intranasal delivery in mice. When administered into the nostrils of healthy mice, human NGF reached the brain, where its levels peaked after three hours, gradually returning to baseline by 16 hours.
The researchers then tested the experimental treatment or a placebo in wild-type (WT) and knockout (KO) male mice, starting at a time when symptoms of Rett syndrome were not yet apparent. Unlike WT mice, which produced the normal levels of MeCP2, KO mice lacked the MECP2 gene and did not produce any of the protein.
Untreated KO mice showed the expected worsening of symptoms, whereas those treated daily for 30 days experienced a delay in disease progression, particularly in terms of tremors and how well they moved and clasped. There was no change in body weight, suggesting no side effects.
In a novel object recognition test, which measures short-term memory by watching how well a mouse can recognize a new object, human NGF was found to improve memory in KO mice. In a marble burying test, which measures exploratory behavior, treatment restored typical digging behavior after 10 and 25 days.
Motor skills such as balance and coordination were checked with a test where mice are timed while descending a pole. Although human NGF did not reduce the time to go down the pole, it did slow the progression of motor decline in KO mice over time.
Life expectancy not increased with human NGF treatment
Despite these improvements in cognitive and motor function, life expectancy was not increased in the KO mice treated with human NGF, “suggesting that the treatment protocol could be refined,” the researchers wrote. Starting treatment at an earlier timepoint resulted in greater improvements, but not longer lifespan.
In female mice, which lack one of the copies of the MECP2 gene and usually have milder symptoms compared with males, a 50-day treatment course with human NGF resulted in better mobility, less tremor, and improved memory.
Molecular analysis revealed that human NGF improved the health and function of mitochondria, the energy-producing structures in cells. This likely contributed to the benefits observed after treatment, according to the researchers.
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