Studies in mice show promise for human treatment of 16p11.2 deletion syndrome

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Research conducted in mice at the University of California Davis MIND Institute suggests that a drug treatment can reverse cognitive deficits and social abnormalities in a rare genetic disorder, 16p11.2 deletion syndrome, which includes symptoms of intellectual disability and autism spectrum disorder, among others.

Results of parallel studies conducted at the MIND (Medical Investigation of Neurodevelopmental Disorders) and at the Massachusetts Institute of Technology (MIT) Picower Institute for Learning and Memory appear in the latest issue of the journal Neuropsychopharmacology.

Our collaborative teams found that treatment with the drug R-baclofen improved scores on several learning and memory tasks, and on a standard assay of social behavior, in 16p11.2 mutant mice.

This corroboration of findings by two independent labs, using two distinct lines of mice with the same mutation, increases confidence that R-baclofen may be an effective pharmacological treatment for some of the symptoms of human 16p11.2 deletion syndrome, including intellectual impairment and autism.

Said MIND Institute researcher Jacqueline Crawley, co-senior author of the paper along with MIT’s Mark Bear.

Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16 at position p11.2. The prevalence in the general population is estimated at three in 10,000.

People with 16p11.2 deletion syndrome may have impaired communication and social skills, as well as delayed development of speech and language and intellectual impairments, recurrent seizures, and an increased risk for obesity. Others with the deletion have no identified physical, intellectual or behavioural abnormalities.

Growing knowledge about genetic mutations in people with autism is enabling researchers to evaluate hypothesis-driven pharmacological interventions for their ability to reverse the biological and behavioural consequence of specific mutations that cause autism.

In the current paper, researchers report the results of animal model studies using two independently derived lines of mutant mice, each missing a chromosomal region analogous to human 16p11.2. Normal and mutant mice at both labs were tested after receiving R-baclofen in their drinking water on three tasks: novel object recognition, object location memory and contextual recognition learning and memory.

Mice of each genotype that received no R-baclofen in their drinking water were used as controls in the experiments. Drug-treated mutant mice scored better after treatment on each cognitive task than the untreated mutant mice.

Remarkably, R-baclofen also increased some scores on a standard assay of mouse social behaviours — male-female reciprocal social interactions — in the 16p11.2 mutant mice.

Crawley said.

Crawley is currently conducting a replication study to determine the robustness of the R-baclofen reversal of behavioural symptoms in mutant mice. Her laboratory is part of a consortium that includes investigators at the University of Pennsylvania, Harvard University and the Institut de Génétique et Biologie Moléculaire et Cellulaire in France. Each of the consortium members is evaluating R-baclofen in different lines of 16p11.2 deletion mice using a variety of assays.

If the preclinical mouse data prove consistently promising, our translational studies may encourage a new clinical trial with the human Arbaclofen compound in people with 16p11.2 deletion syndrome.

Said Crawley.

The consortium’s research project is supported by the Simons Foundation, which leads a major research initiative focused on people with 16p11.2 deletion syndrome.

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