overview: Researchers have developed a new treatment that could potentially be used to treat patients with the autistic subtype of Phelan-McDiarmid syndrome.
sauce: Northwestern University
A team of researchers in the Northwest, led by Dr. Peter Penzeth, Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences and Director of the Center for Autism and Neurodevelopment, has developed a new treatment that could treat Phelan-McDiarmid syndrome. .Subtypes of Autism Spectrum Disorder (ASD), according to findings published in molecular psychiatry.
According to the Centers for Disease Control and Prevention, 1 in 44 children in the United States is diagnosed with ASD, and each sufferer has a range of symptoms, including speech delays, motor and learning abilities, epilepsy, and poor diet and sleep. Shows clinical and developmental symptoms. habits, and gastrointestinal problems.
Phelan-McDermid syndrome is known to be caused by specific genetic mutations in SHANK3, a well-known ASD candidate gene. The heterogeneity of ASD makes the development of effective targeted therapies extremely challenging, leaving patients with therapeutic options to improve disease management.
Based on the urgent need for new therapies, Penzes’ team developed derivatives of the insulin-like growth factor binding protein IGFBP2. IGFBP2 is found in brain structures affected by ASD and has been shown to improve neuroplasticity and cognitive function.
In the current study, researchers administered an IGFBP2-derived peptide called JB2 to mice with the SHANK3 mutation. Through advanced brain imaging, they found that the drug improved neuroplasticity, behavioral deficits, and cellular processes in the mouse brain.
These changes directly correlated with improvements in the mice’s learning and memory abilities, motor function, and ultrasonic vocalization communication, Penzes said.
“These ultrasonic vocalizations of mice somehow model those of mice because speech is either not developed at all, or is very slow to develop, or is so simplistic in autistic patients. It is thought that there is,” said Penzes, who is also a professor of neuroscience. and pharmacology.
Using an electroencephalograph to measure brain activity in the mice, the team also found that JB2 normalized neuronal excitability, how neurons respond to stimulation with electrical charges, and susceptibility to seizures. did.
The drug is still in its early stages, but in theory, it would be ideal to have the drug regularly injected into a patient’s bloodstream at a young age in the form of regular injections or pills, Penzes said. increase.
“Because it is a neurodevelopmental disorder, the brain changes after birth and into adulthood. is more difficult,” Penzes said.
Penzes said early clinical trials will include participants with Phelan-McDiarmid syndrome and, if successful, could eventually be expanded to include patients with other types of ASD.
“It’s hypothesized that similar changes occur in the brains of other types of autism and those with Phelan-McDiarmid syndrome, but those patients would respond better,” Penzes said. Stated.
About this ASD and genetics research news
author: Mara Paul
sauce: Northwestern University
contact: Marla Paul – Northwestern University
image: image is public domain
Original research: open access.
Jeffrey S. Burgdorf et al. molecular psychiatry
Peptides derived from IGFBP2 promote neuroplasticity and rescue defects in a mouse model of Phelan-McDiarmid syndrome
We developed an IGFBP2 mimetic peptide fragment, JB2, and showed that it promotes structural and functional plasticity of basal synapses in cultured neurons and mice.
We show that JB2 directly binds to dendrites and synapses and that its biological activity involves NMDA receptor activation, gene transcription and translation, and the IGF2 receptor. Not IGF1 receptor dependent. In neurons, JB2 induced massive remodeling of the membrane phosphoproteome.
Synaptic and cytoskeletal regulation, risk factors for autism spectrum disorders (ASD), and Shank3-associated protein networks were significantly enriched between phosphorylated and dephosphorylated proteins.
Haploinsufficiency of Shank 3 A gene on chromosome 22q13.3 often causes Ferran-McDiarmid syndrome (PMS), a genetically defined autism disorder with severe impairments in motor behavior, sensory processing, language, and cognitive function. .
We identified multiple disease-associated phenotypes. Shank 3 In heterozygous mice, we showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalization, and motor function. It also normalized neuronal excitability and seizure susceptibility.
Notably, JB2 rescued deficits in auditory evoked response latencies, alpha peak frequencies, and steady-state EEG responses, with direct translational value in human subjects.
These data indicate that JB2 is a potent modulator of neuroplasticity and has therapeutic potential for PMS and ASD.