After 5 intensive days at the annual meeting held this year in New Orleans, things are just getting back to normal around here. Among the >28,000 participants, there were several presentations that particularly caught my eye in the areas of autism, schizophrenia and multiple sclerosis.
In the autism realm, Susan Masino of Trinity College in Connecticut tested the effects of the ketogenic diet (KD) on a mouse model with autistic features, the BTBR strain. This diet is a high fat, low carbohydrate regimen that has proven quite useful in treating pediatric and drug-resistant epilepsy. Since ~1/3 of autism spectrum disorder (ASD) children have seizures, it is logical to test this diet on the BTBR mice. Five week-old mice were fed a control or a KD for 3-5 weeks and then tested for several ASD-relevant behaviors. Those on the KD displayed improved social interaction behaviors and fewer repetitive behaviors. This diet did not have a detectable effect on these behaviors in a standard lab mouse strain (C57Bl/6). The authors concluded, “We suggest that the KD be considered as a treatment opportunity for autism, particularly in cases with comorbid epilepsy in which the diet could have a dual benefit of reducing seizures and improving symptoms of autism.”
M.R. Pitcher, J.L. Neul and colleagues at Baylor College of Medicine tested a new formulation of insulin-like growth factor 1 (IGF1) in a mutant Mecp2 mouse model of Rett syndrome. Mutations in Mecp2 cause Rett. Recall from my book and from prior posts here that a small IGF1 peptide has very positive effects on Rett symptoms in a mutant Mecp2 mouse model, and that this led to the current clinical trials of IGF1 in human Rett patients. These trials use the full length, complete IGF1 rather than the smaller, truncated form that was used in the mice. This is because the latter form is not yet approved by the FDA while the full length form was already approved for treatment of short stature and is believed to be safe. In the work by Pitcher, a new formulation was tested, which is more stable and would therefore require less frequent injections. Unfortunately, a low dose of this drug had no effect on symptoms in the mice, while a high dose had detrimental effects, including a significant decrement in survival time. Meanwhile, the group of Mrganka Sur at MIT reported that treatment of Mecp2 mutant mice with the full length version of IGF1 was less effective than the short version. These new results are cause for worry about the outcome of the clinical trials of the full length form of IGF1.
On the schizophrenia front, certain variants of the gene neuregulin (NRG1) have been linked to increased risk for schiz. D. Yin and colleagues at the Georgia Health Sciences University reported on a new mouse strain in which NRG1 can be experimentally controlled, specifically in certain neurons in the brain (pyramidal neurons in the forebrain). They find that turning up NRG1 levels in these cells during development results in adults with hyperactivity, impaired memory and decreased prepulse inhibition (relevant for schiz and autism). Importantly, turning down NRG1 in the mice that already display these symptoms causes the symptoms to recede. In the converse experiment, they turned up the level of NRG1 in adult mice and found that the schiz-like symptoms could be induced. These results suggest at least two intriguing conclusions: First, the level of NRG1 in specifically in pyramidal neurons can control behavior, and second, the adult brain is plastic and can respond to modifications in NRG1 with significant changes in behavior. As I pointed out in my book, and in past posts here, similar findings of adult brain plasticity have been made in mouse models of Rett syndrome, tuberous sclerosis and fragile X syndrome. All of these findings offer reasons for optimism for ameliorating symptoms in patients.
P.M. Grace of the group of Linda Watkins and Steve Maier at the University of Colorado at Boulder reported a very promising approach to treating multiple sclerosis. Using a rat EAE (experimental autoimmune encephalomyelitis) model, they tested the anti-inflammatory cytokine IL-10 by encapsulating its gene in slow-release microparticles that gradually degrade after injection intrathecally (similar to spinal tap injection). This approach would presumably allow a long-lasting increase in IL-10 levels in the spinal cord and possibly in the brain. When this drug formulation was injected at the time of onset of behavioral symptoms, it increased voluntary exercise (wheel running) and social exploration, and decreased debilitating motor symptoms and pain sensitivity. Most striking was the effect of IL-10 on survival: at the time when 40% of the EAE rats had prematurely died, the IL-10-treated EAE rats were all alive. Clearly, this drug formulation merits further exploration.