Tismoo's pioneerism on personalized therapeutic perspectives for Autism Spectrum Disorder
This week is celebrated the Ninth Annual World Autism Awareness Day. Every year, on April 2, autism organizations around the world celebrate the day with unique fundraising and awareness-raising events.
Autism is a complex syndrome that affects three important areas of a person's development: communication, socialization and behavior. It still has no cure and can present itself at several different levels of impairment. Though No person has yet being cured from Autism, according to many studies and researches done so far, we can no longer assume that its cure is unviable. So, in a sense, saying that autism is incurable would be misleading and unrealistic; and senior author and associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine, founder of Tismoo,Alysson Muotri, PhD, agrees with it.
Dr. Muotri founded Tismoo as the first laboratory in the world exclusively devoted to genetic analyzes centered on personalized therapeutic perspectives for Autism Spectrum Disorder and other neurological disorders of genetic origin such as Rett Syndrome, Timothy Syndrome, Fragile X Syndrome, Angelman Syndrome And Phelan-McDermid Syndrome and the Zika Virus, amongst many others.
Tismoo began its activities with the aim of bringing the techniques and studies of the forefront, previously restricted to the universities, and put them into practice for the clinical benefit of the individuals affected by these conditions. Its goal is to recreate in the laboratory the stages of neural development from the patient's own cells - "mini-brains" - capable of capturing the genetic material of each individual.
The “mini-brains”, have gained global prominence in the media.
Built with induced pluripotent stem cells derived from patients with a rare, but devastating, neurological disorder, have helped a lot in the search to understand diverse syndromes and diseases, besides the autism, identifying a drug candidate that appears to “rescue” dysfunctional cells by suppressing a critical genetic alteration.
As published on the Molecular Psychiatry magazine, the neurological disorder is called MECP2 duplication syndrome and it was first described in 2005, being caused by duplication of genetic material in a specific region of the X chromosome that encompasses MECP2 and adjacent genes. The disorder displays a wide variety of symptoms, among them low muscle tone, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, autistic behaviors and potentially severe intellectual disability. It is heritable, but can also occur randomly. MECP2 duplication syndrome occurs almost exclusively in males, but a similar disorder known as Rett (RTT) Syndrome, which involves MECP2 gene deletions, primarily affects females. Current treatment is largely symptomatic, involving therapies, drugs and surgeries that address specific issues.
As in previous, ground-breaking research with Rett Syndrome patients, Dr. Muotri, and colleagues took skin cells from MECP2 duplication patients, converted them into induced pluripotent stem cells (iPSC), and then programmed the stem cells to become neurons that recapitulate the disorder more robustly than existing mouse models.
“Analyses of the iPSC-derived neurons revealed novel molecular and cellular phenotypes, including an over-synchronization of the neuronal networks. Interestingly, these phenotypes go in a direction opposite of what scientists had previously reported for Rett syndrome, suggesting that the correct gene dosage is important for homeostasis in human neurons," said the doctor, “But More importantly,” he continued,” the finding with human neurons helped direct the next stage, a drug screening, which uncovered a drug candidate – a histone deacetylase inhibitor that reversed all the MECP2 alterations in the mutant neurons, with no harm to control neurons." He continued.
“This work is encouraging for several reasons,” highlighted Dr. Muotri, “First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.”
"The great advantage of this kind of process is that we begin to open up a viable possibility for drug testing, without using the patient himself as a guinea pig. By using these 'mini-brains' it is possible to test the types and quantities of drugs and thus define a more appropriate treatment for each individual, "explains Dr. Muotri, currently considered one of the world's leading experts on autism.
In the midst of innumerous equipment, the “transdiciplinar” Tismoo’s lab, located, in Torrey Pines, at the University Of California San Diego (UCSD), also counts with the help of couple of notorious machines, such as, a multi-electrode which allows Dr.Alysson Muotri’s team of researchers to listen to the “mini-brains” electric activity when a culture of neurons is placed on a plaque.
Besides the multi-electrode, Tismoo also uses an ingenious and contemporary electric microscopic, where it’s possible to observe synapses as they occur with the use of a fluorescent “marker”, considering, of course, that these electric impulses are not visible to the naked eye. “It’s somewhat, alike Astronomy”, humored the neuroscientist, “When you look at the sky you don’t get to see the stars, in their entirety, right away. You’d need to enhance the signal so that the stars can be studied; the same happens in our brains. Once you can observe that snapshot, you are able to quantify the amount of synapses and how they’re formed. We’re able to witness it over time; we watch these cultures since their primordial moments, when they’re very immature, until they expand their complexity and increase the number of synapses that can be performed.”
Another remarkable apparatus is a morphometric analysis microscope, which allows the scientists to analyze in detail the anatomy of a neuron, to the point of being able to measure its dendrites, ramifications, and nucleus. It was using this technology that Dr. Muotri was able to scrutinize, for the first time, that the neurons on autism patients had a much different morphology, stagnating their growth in a given development period, which prevented these neurons from achieving maturity, and thus, not becoming able to do as many synapses as healthy neurons. “In a normal development, you can see that synapses’ complexity increase, which causes to shape a huge variety of human behavior that we use to communicate and relate ourselves to the world; whereas the neurons with autism does not experience the same, just like if these same neurons were simply blocked”- Dr. Alysson Muotri elaborated - “The accuracy of these equipment also permit our research to even further our tests with some pre-established substances which we believe that would enable these neurons to advance their growth passing their stagnation point, watching it over time for their effectiveness.”
The neuroscientist also suggested that his research could help finding the cure for Schizophrenia and other psychiatric diseases as well, “What we realize is that when we repair the number of synapses, it ends up repairing the communication networks formed by the neurons. My point of view is even more comprehensive: that any genetic disease, whose problem is in the synapse, we will be able to correct at some point.”
"I believe we are facing significant challenges today, as in the case of Autism. We need new business models that are able to intelligently reconcile the interests of their investors to a greater purpose and provide positive and sustainable change in society "This is what we are living at TISMOO today and it is our motivation for the new challenges that are to come," concludes Muotri.
Dr. Alisson Muotri has more than impressive credentials. He graduated in Biological Sciences from the State University of Campinas (Unicamp) in 1995, and received his PhD in Genetics from the University Of São Paulo (USP) in 2001, and is a postdoctoral fellow in Stem Cells and Neurosciences by the Salk Research Institute in La Jolla, USA, becoming professor of the University Of California School Of Medicine in 2008. His research uses stem cells to understand the development and evolution of the human brain and he pioneered the use of human embryonic stem cells, creating the first chimeric animal with human neurons. It also warned the global scientific community about the contamination of animal products in these cells. The neuroscientist also developed the first cellular model to study autistic neurons, signaling a possible reversal of the condition through new drugs with the research being published in high-impact scientific journals such as Nature and Cell. Dr. Moutri has received several international awards, including the prestigious Director's New Innovator Award from the National Institutes of Health (NIH), USA.