Stem cell technology developed at UWMadison leads to new understanding of Autism risks – University of Wisconsin-Madison

RosetteArrays, developed at UWMadison, grow fields of neural rosettes embroynic versions of down-scaled, simplified brain structures from stem cells, giving scientists the opportunity to study the development of disorders like autism, spina bifida and epilepsy. Image courtesy of Neurosetta

Technology developed at the University of WisconsinMadison to grow rosettes of brain and spinal tissue gives scientists new ways to study the growing human brain, including a recent study of how genetic mutations linked to autism affect early stages of human brain development.

Its the latest discovery using RosetteArray technology, a screening tool that uses stem cells to generate embryonic forebrain or spinal cord tissue structures called neural rosettes. Neural rosettes are the starting material for generating human stem cell-derived neural organoids clusters of cells that resemble larger, more complex organs and can be used to assess whether different genetic makeups or exposure to chemicals increase the risk of neurodevelopmental disruptions.

Randolph Ashton

This technology gives us access to an embryonic model of human central nervous system development that we would otherwise not have access to, says Randolph Ashton, a UWMadison professor of biomedical engineering and associate director of the Stem Cell and Regenerative Medicine Center. This is useful, because not only can we now understand more about human development, but we can get an understanding of when it goes wrong.

Ashton and Gavin Knight, a scientist at the Wisconsin Institute for Discovery who earned his doctorate in Asthons lab, developed the technology behind RosetteArrays, which are marketed by Neurosetta, a company they co-founded with support from UWMadison Discovery to Product and the Wisconsin Alumni Research Foundations (WARF) Accelerator Program.

RosetteArray technology played an important role in a study published recently in Nature Neuroscience. The study, led by University of Southern California stem cell biologist Giorgia Quadrato, with Ashton and Knight as co-authors, investigated mutations of a gene called SYNGAP1.

SYNGAP1 mutations have long been associated with risk factors for autism spectrum disorder, epilepsy, neurodevelopmental disability and more, but until now the gene has mainly been studied in animal models and focued on the impact of SYNGAP1 on synapses, the structure at the tips of long brain cells called neurons that allow them to pass signals to neighboring cells.

In their new SYNGAP1 autism study, Quadrato and her lab used RosetteArray technology to grow neural rosettes from healthy human cells as well as from the cells of a patient with a disease-causing variant in SYNGAP1. By analyzing these young, developing neural organoids, Quadrato determined that human radial glia cells the cells responsible for producing all the neurons in the outer layer of the brain called the cerebral cortex can express SYNGAP1. When SYNGAP1 is mutated, it leads to disrupted organization of the cortical plate, an early brain structure that gives rise to the cerebral cortex. This shows that SYNGAP1-related brain disorders can arise through non-synaptic mechanisms.

Quadrato Lab and Neurosetta plan to partner on further studies to explore the extent of autism spectrum disorder genetic backgrounds that can be modeled using RosetteArray technology, which Ashton hopes will eventually lead to new precision medicine approaches.

Simply being able to model early human development, in this case brain and spinal cord formation, gives you a very powerful platform to try to improve human health, says Ashton. Weve been surprised to see the effects of neurological disease-causing mutations in the earliest stages of these tissues formation. RosetteArrays model approximately four to six weeks post conception, and were learning that you can start to see markers for autism then, which is a disease that people typically arent diagnosed with until post 2 years of age. So, the fact that we can see this very early in our model of human development is amazing.

Ashton says researchers using technologies like the RosetteArray are finding that the risk factors for autism spectrum disorder are boiling down to a couple of core pathways, that seem to have roles very early in human brain development, which is helpful information as researchers work on treatments.

While this paper focused on studying brain tissue, Ashton has used the RosetteArray platform in his own lab to study defects in neural tube formation.

(The neural tube) is a structure that goes from the head of the embryo all the way down through the back of the spinal cord. All brain, spinal cord and eye tissue comes from this neural tube, says Ashton. It so happens that a lot of things can disrupt that process, and if that formation is disrupted early enough, then it causes lots of issues. It can cause congenital birth defects known as neural tube defects, for example spinal bifida, which is when the lower spine doesnt fully close. Or, if you have a failure of closure higher in the neural tube that leads to a failed pregnancy, so understanding this process is crucial.

Ashton and his lab members have been using RosetteArrays to investigate what may be causing spina bifida defects and how they can be mitigated.

There are examples of known chemicals we use in our food supply, pesticides, and anti-cancer drugs that have historically been correlated with causing neural tube defects. So, its important that we have a way to test new chemistries and chemical processes to make sure they dont have these effects on human development, says Ashton. Weve used rodent models but theres a difference between animals and humans. The RosetteArray provides a way to test these chemicals on early human brain and spinal cord development.

The RosetteArray platform may also be used for individualized medicine, as it can be used to screen individual patients cell lines to better understand how mutations in a persons genomic background can lead to a disorder as well as how the interaction between a persons genomic background and the chemicals that theyre exposed to may lead to a health risk.

We think this platform will be highly useful for both commercial applications for screening for chemicals that can cause neurodevelopmental risk, as well as for clinical application, Ashton says. And I think the real power of the tool is for precision medicine and drug discovery.

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Stem cell technology developed at UWMadison leads to new understanding of Autism risks - University of Wisconsin-Madison

Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease – Yale Medicine

Until recently, the only possible cure for sickle cell disease, an inherited genetic blood disorder most common in people with African ancestry, was a bone marrow transplant, which has its own set of challenges.

Now, people with sickle cell disease (SCD)which affects an estimated 100,000 Americans and can cause chronic pain, organ damage, strokes, and shortened life expectancyhave additional, potentially curative options. In early December, the Food and Drug Administration (FDA) approved two gene therapies for SCD, one of which is the first approved medication that uses the gene-editing tool CRISPR.

Both treatmentsCasgevy, which is made by Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia, by Bluebird Bioare for people 12 and older. Sickle cell disease is a red blood cell disorder that affects hemoglobin, the protein that carries oxygen throughout the body. These two therapies work in different ways, but both are intended to be a one-time fix, although that will require years of follow-up to know for sure.

With Casgevy, an edit (or cut) is made in a particular gene to reactivate the production of fetal hemoglobin, which dilutes the faulty red blood cells caused by sickle cell disease (more on that below). Lyfgenia, on the other hand, uses a viral envelope to deliver a healthy hemoglobin-producing gene.

The therapies are hailed as groundbreaking as they represent the first-ever gene therapies to potentially cure a hereditary condition.

For many years, we only had one treatment for sickle cell disease, and then medicine advanced to the point where we could offer bone marrow transplant, the first potential cure for sickle cell disease, says Cece Calhoun, MD, MBA, a Yale Medicine hematologist-oncologist. But trying to find a good match for a transplant is a big barrier. This new technology uses gene therapy to allow patients to be their own match.

This is significant, she notes, because a sickle cell crisisthe pain the disease causesis unpredictable and intense, akin to how it feels to have a long bone fracture.

But, says Dr. Calhoun, the pain sickle cell disease causes is not the only problem faced by people with the condition.

Sickle cell disease impacts every organ. Children are having strokes, and young adultspeople in their 30sare experiencing kidney failureall because of sickle cell disease. If we can intervene and prevent these complications and let these patients live full lives, that is huge, Dr. Calhoun says.

Lakshmanan Krishnamurti, MD, chief of Yale Medicine Pediatric Hematology & Oncology, agrees.

Many cant have bone marrow transplantation because only about 15% of patients have a matched sibling, and we can find an unrelated donor for only another 10% to 12%. That means we are only helping 25% of patients, says Dr. Krishnamurti, who was an author on the Lyfgenia study published in The New England Journal of Medicine. This is a big step forward.

However, the gene therapies are time-intensivetaking about a year to complete the processand grueling. As with bone marrow transplants, they require high-dose chemotherapy to kill the faulty stem cells before they are replaced with modified stem cells.

The gene therapies will be available only at large, authorized medical centers because they require advanced care. They are also expensive (estimates put it at $2 to $3 million per patient), and its yet to be determined if or how insurance companies, including Medicaid, will cover the treatment.

Dr. Krishnamurti says both treatments will be available at Yale and that anyone interested in learning more should speak to their physician.

Below, Drs. Calhoun and Krishnamurti answer common questions about sickle cell disease and these new gene therapies.

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Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease - Yale Medicine