Patient-Specific Neurons Reveal Vital Clues About Autism


The brains of some people with autism spectrum disorder grow faster than usual early on in life, often before diagnosis. Now new research from scientists at the Salk Institute has used cutting-edge stem cell-based techniques to elucidate those mechanisms that drive excess brain growth, which affects as many as 30 percent of people with autism.

These findings show that it is possible to use stem cell reprogramming technologies to model the earliest stages of complex disorders and to evaluate potential therapeutic drugs. The Salk team, led by Alysson Muotri, discovered that stem cell-derived neurons, derived from stem cells that had been made from cells taken from autism patients, made fewer connections in culture compared to cells from healthy individuals. These same scientists also restored cell-cell communication between these cells by adding a growth factor called IGF-1 (insulin-like growth factor-1). IGF-1 is in the process of being evaluated in clinical trials of autism.

“This technology allows us to generate views of neuron development that have historically been intractable,” said senior investigator Fred H. Gage. “We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

In the United States alone, autism affects approximately one out of every 68 children. Autistic children have problems communicating, show an inhibited ability to interact with others, and usually engage in repetitive behaviors. Mind you, the symptomatic manifestations in autistic children can vary dramatically in type and severity. Autism, to date, has no known, identified cause.

In 2010, Gage and collaborators recreated features of Rett syndrome (a rare disorder that shares features of autism but is caused by mutations in a single gene; MECP2) in a cell culture system. They extracted skin cells from Rett Syndrome patients and converted those cells into induced pluripotent stem cells (iPSCs). Then Gage and others differentiated those Rett-Syndrome-specific iPSCs into neurons, which they grew in culture. These neurons were then studied in detail in a neuron-specific culture system. “In that study, induced pluripotent stem cells gave us a window into the birth of a neuron that we would not otherwise have,” said Marchetto, the study’s first author. “Seeing features of Rett syndrome in a dish gave us the confidence to next study classical autism.”

In this new study, Gage and others created iPSCs from autism patients whose brains had grown up to 23 percent faster than usual during toddlerhood but had subsequently normalized. These iPSCs were then differentiated into neuron precursor cells (NPCs). Examinations of these NPCs revealed that the NPCs made from iPSCs derived from autism patients proliferated faster than those derived from typically developing individuals. This finding supports a theory advanced by some experts that brain enlargement is caused by disruptions to the cell’s normal cycle of division, according to Marchetto.

In addition, the neurons derived from autism-specific iPSCs behaved abnormally in culture. They fired less often compared with those cells derived from healthy people. The activity of these neurons, however, improved if they were treated with IGF-1. IGF-1 enhances the formation of cell-cell connections between neurons, and the establishment and stabilization of these connections seem to normalize neuronal function.

Muotri and Gage and others plan to use these patient-derived cells to elucidate the molecular mechanisms behind IGF-1’s effects. They will examine changes in gene expression and attempt to correlate them with changes in neuronal function. Although the newly derived cells are far from the patients’ brains, a brain cell by itself may, hopefully, reveal important clues about a person and their brain.

This work was published in the journal Molecular Psychiatry: M. C. Marchetto et al., “Altered proliferation and networks in neural cells derived from idiopathic autistic individuals,” Molecular Psychiatry, 2016; DOI: 10.1038/mp.2016.95.

FDA Approves Clinical Trial that Used Cord Blood to Treat Autism


The Sutter Neuroscience Institute in Sacramento, California has announced its collaboration with the Cord Blood Registry, the world’s largest stem cell bank in what promises to be the first FDA-approved clinical trial to assess the use of a child’s own cord blood stem cells to treat selected patients with autism. This placebo-controlled study is the first of its kind and will evaluate the efficacy of cord blood stem cells to help improve language and behavior in autistic children.

The Centers for Disease Control (CDC) places the frequency of autism in the US as one in 88, but for boys, the rate is even higher (1 in 54). Autism, today, is part of a series of conditions that are collectively defined as autism spectrum disorders (ASPs). ASPs include individuals with very different symptoms, and include everything from autistic disorder (also known as classic autism, Asperger syndrome and pervasive developmental disorder not otherwise specified (also known as atypical autism). These conditions are thought to have multiple risk factors that include genetic, environmental and immunological components.

With regard to this study, Michael Chez, M.D., director of Pediatric Neurology with the Sutter Neuroscience and principal study investigator of this clinical trial said: “This is the start of a new age of research in stem cell therapies for chronic diseases such as autism, and a natural step to determine whether patients receive some benefit from an infusion of their own cord blood stem cells. I will focus on a select portion of children diagnosed with autism who have no obvious cause for the condition, such as known genetic syndromes or brain injury.”

This clinical study will enroll 30 children between the ages of two and seven who have been diagnosed with autism, and meet all the criteria for inclusion in the study. Over the course of this clinical trial, all enrolled participants will receive two infusions over the course of 13 months. One of the infusions will contain the child’s own cord blood stem cells, and the other infusion will contain a placebo. The participants and the lead investigators will not know the content of each infusion. To ensure the highest quality and consistency in cord blood stem cell processing, storage and release for infusion, Cord Blood Registry is the only family stem cell bank that provides umbilical cord blood units from clients for the study.

A newborn’s umbilical cord blood contains several unique populations of stem cells. Scientists and physicians have been used for more than 20 years in medical practice to treat certain cancers, blood diseases and immune disorders. When patients undergo a stem cell transplant for such conditions, the umbilical cord blood stem cells effectively rebuild the blood and immune systems.

According to Dr. Chez, “A focus of my research has been the complex relationship between a child’s immune system and central nervous system. We have evidence to suggest that certain children with autism have dysfunctional immune systems that may be damaging or delaying the development of the nervous system. Cord blood stem cells may offer ways to modulate or repair the immune systems of these patients which would also improve language and some behavior in children who have no obvious reason to have become autistic. The study is similar to other FDA-approved clinical trials looking at cord blood stem cells as a therapy for cerebral palsy.”

Heather Brown, vice president of scientific & medical affairs at Cord Blood Registry, said: “It’s exciting to partner with thought-leading medical researchers and clinicians, like Dr. Chez, who are pursuing a scientifically-sound approach in evaluating new therapeutic uses for cord blood stem cells for conditions that currently have no cures. Families who made the decision to bank their stem cells to cover the unknowns and what ifs in life are gaining access to this and other important clinical trials while playing an important role in the advancement of science.”

A co-investigator of the study is Michael Carroll, M.D., who is the medical director of the Blood and Marrow Transplantation and Hematological Malignancies Program at Sutter Medical Center, Sacramento. According to Dr. Carroll, “There is a vast amount of unchartered territory when it comes to how stem cell therapies may help patients living with these conditions. I’ve seen how stem cell therapy has changed my field of medicine and how I care for my blood cancer patients. I am eager to see how our work can open new doors for patients and families dealing with autism.”