Arrested Development: A brain organoid derived from the skin cells of a child with Pitt-Hopkins syndrome (right) is smaller and has fewer neurons than that derived from a child without the syndrome (left).
Tiny balls of cultured human brain cells reveal how genetic mutations linked to Pitt-Hopkins syndrome, a profound form of autism, disrupt brain development, according to a new study. These balls of cells called brain organoids also reveal how gene therapies might help lessen the mutations effects.
The data offers hope that a future clinical application with gene therapy might actually benefit certain autism spectrum disorder patients, says co-lead investigator Alysson Muotri, professor of pediatrics and of cellular and molecular medicine, and director of the stem cell program, at the University of California, San Diego. Our research is focused on profound autism spectrum disorder subtypes individuals that really need help and medical support to achieve their full potential.
Pitt-Hopkins syndrome is caused by de novo mutations in TCF4, a gene that controls when other genes are turned on or off in the embryo and is essential for brain development. Children with Pitt-Hopkins syndrome have severe cognitive and motor disabilities and typically are nonverbal.
There is a rough estimate that Pitt-Hopkins syndrome affects 1 in every 30,000 individuals, but this is an underestimate, because genetic diagnostic testing is not available in most countries, says co-lead investigator Fabio Papes, associate professor of genetics, evolution, microbiology and immunology at the University of Campinas in So Paulo, Brazil.
Papes has a relative with Pitt-Hopkins syndrome, which spurred him to study how TCF4 mutations impair brain development. He and Muotri turned to organoids because mouse models of the condition are limited: The animals display some Pitt-Hopkins syndrome-like traits, such as impairments in social interactions and memory, but fail to mimic the severe traits seen in people.
The new results highlight once more, the need for human models in order to fully understand the genetics of neurodevelopmental disorders, says Jrgen Knoblich, scientific director of the Institute of Molecular Biotechnology at the Austrian Academy of Sciences in Vienna, Austria, who did not take part in this research. It represents nice and useful progress for the field of neurodevelopmental disorders.
Muotri, Papes and their colleagues generated brain organoids using skin cells from five children with Pitt-Hopkins syndrome and five controls.
After four weeks, organoids with TCF4 mutations were significantly smaller than those without, and many of their cells had not developed into neurons from precursor cells called neural progenitors.
The neural progenitors exhibited arrested development, likely due to a disruption in a cell signaling pathway called WNT and then reduced expression of a gene called SOX, the scientists found. Compared with controls, the progenitors yielded fewer cortical neurons, which power thinking, memory, speech and other cognitive abilities. And the neurons they did produce showed impaired electrical activity and tended to cluster together instead of self-organizing into neural circuits. The findings appeared in Nature Communications in May.
It is surprising to see such significant effects on neural progenitor cells, because the obvious traits of Pitt-Hopkins syndrome, such as microcephaly, or a small head, usually develop after birth, says Ben Philpot, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who did not work on this study. This suggests that their organoid model was highly sensitive and has great value for screening potential therapeutics, he says.
The scientists also tested two different virus-based gene therapies on the organoids. One encodes molecules that boost levels of TCF4 protein, whereas the other delivers a functional copy of the gene to the cells. Both techniques resulted in organoids that resembled the controls.
We could rescue molecular, cellular and neural network alterations by just restoring the expression of the corrected gene, Muotri says.
In an unrelated study published in eLife in May, Philpot and his colleagues tested a very similar gene therapy strategy in mouse models, Papes says. Both papers complement each other very nicely, providing very solid evidence, in patient-derived human cells and in animals, that gene therapy is possible for this form of profound autism.
Muotri, Papes and their colleagues have partnered with a pharmaceutical company specializing in gene therapy to use these new findings to design a clinical trial. The clinical potential is huge, Muotri says. We will start with TCF4, but our strategy allows us to test other genes implicated in autism spectrum disorder.
The scientists caution that these findings may not translate for people with Pitt-Hopkins syndrome. A brain organoid is not a mini-brain, Muotri says. These are really small structures when compared to the human brain. Also, they are mimicking developmental stages rather than a more mature human brain.
In addition, children enrolled in a clinical trial would receive the gene therapies a few years after the prenatal stage of brain development in which the therapies were tested. Our gene therapy approach may not correct all characteristics, especially those changes that cannot be reverted once the cells and brain tissue have already been altered, Papes cautions.
Before clinical trials can ever happen, we need to be absolutely convinced that our methods will cause no harm and will be effective, Muotri says. Thus, we have a lot of work to do in the following years.
Cite this article: https://doi.org/10.53053/FQVM6681
Here is the original post:
Organoids test gene therapies for Pitt-Hopkins syndrome - Spectrum
- New gene offers hope for preventive medicine against fractures [Last Updated On: September 18th, 2012] [Originally Added On: September 18th, 2012]
- Colon Cancer Gene Database May Assist Research Efforts [Last Updated On: September 30th, 2012] [Originally Added On: September 30th, 2012]
- Researchers discover gene that causes deafness [Last Updated On: September 30th, 2012] [Originally Added On: September 30th, 2012]
- Gene Study Yields New Clues to Breast Cancer [Last Updated On: September 30th, 2012] [Originally Added On: September 30th, 2012]
- Gene key to chemotherapy efficacy [Last Updated On: September 30th, 2012] [Originally Added On: September 30th, 2012]
- Gene clues offer new hope for treating breast cancer [Last Updated On: September 30th, 2012] [Originally Added On: September 30th, 2012]
- Gene that causes deafness pinpointed [Last Updated On: October 1st, 2012] [Originally Added On: October 1st, 2012]
- Gene that causes a form of deafness discovered [Last Updated On: October 1st, 2012] [Originally Added On: October 1st, 2012]
- Novel gene associated with Usher syndrome identified [Last Updated On: October 2nd, 2012] [Originally Added On: October 2nd, 2012]
- Translational Regenerative Medicine: Market Prospects 2012-2022 [Last Updated On: October 2nd, 2012] [Originally Added On: October 2nd, 2012]
- Two-day test can spot gene diseases in newborns [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Fast Gene Screen May Help Sick Babies [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Gene therapies need new development models [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Rapid gene machines used to find cause of newborn illnesses [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Gene behind many spontaneous breast cancers identified [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Gene responsible for many spontaneous breast cancers identified [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Two-day test can spot gene diseases in newborns - Wed, 03 Oct 2012 PST [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Researchers Discover Gene Defect Linked to Deafness [Last Updated On: October 3rd, 2012] [Originally Added On: October 3rd, 2012]
- Gene diseases in newborns unveiled quicker [Last Updated On: October 4th, 2012] [Originally Added On: October 4th, 2012]
- Quicker gene test may help babies - Thu, 04 Oct 2012 PST [Last Updated On: October 4th, 2012] [Originally Added On: October 4th, 2012]
- Rapid gene-mapping test may diagnose disease in newborns [Last Updated On: October 5th, 2012] [Originally Added On: October 5th, 2012]
- 2-day test can spot gene diseases in newborns [Last Updated On: October 5th, 2012] [Originally Added On: October 5th, 2012]
- Gene diseases in newborns spotted with 2-day test [Last Updated On: October 5th, 2012] [Originally Added On: October 5th, 2012]
- Rare Gene Deletion Tied To Psychiatric Disease And Obesity [Last Updated On: October 10th, 2012] [Originally Added On: October 10th, 2012]
- Mount Sinai researchers discover gene signature that predicts prostate cancer survival [Last Updated On: October 10th, 2012] [Originally Added On: October 10th, 2012]
- Test Spots Newborn Gene Disease [Last Updated On: October 10th, 2012] [Originally Added On: October 10th, 2012]
- Gene signature predicts prostate cancer survival [Last Updated On: October 11th, 2012] [Originally Added On: October 11th, 2012]
- Researchers Discover Gene Signature that Predicts Prostate Cancer Survival [Last Updated On: October 11th, 2012] [Originally Added On: October 11th, 2012]
- Bioethics Panel Urges More Gene Privacy Protection [Last Updated On: October 11th, 2012] [Originally Added On: October 11th, 2012]
- High Levels of Blood-Based Protein Specific to Mesothelioma [Last Updated On: October 11th, 2012] [Originally Added On: October 11th, 2012]
- Gene clues to help tackle skin disease [Last Updated On: October 15th, 2012] [Originally Added On: October 15th, 2012]
- Additive effect of small gene variations can increase risk of autism spectrum disorders [Last Updated On: October 15th, 2012] [Originally Added On: October 15th, 2012]
- 2-gene test predicts which patients with heart failure respond best to beta-blocker drug [Last Updated On: October 16th, 2012] [Originally Added On: October 16th, 2012]
- Two-gene test predicts which patients with heart failure respond best to beta-blocker drug [Last Updated On: October 16th, 2012] [Originally Added On: October 16th, 2012]
- Gene Linked to Kidney Failure [Last Updated On: October 17th, 2012] [Originally Added On: October 17th, 2012]
- Nanoparticles seen as gene therapy advance [Last Updated On: October 17th, 2012] [Originally Added On: October 17th, 2012]
- Stem Cell Therapy for Sickle Cell Anemia - Video [Last Updated On: October 31st, 2012] [Originally Added On: October 31st, 2012]
- Sickle Cell Anemia: Stem Cell Gene Therapy - Donald Kohn - Video [Last Updated On: October 31st, 2012] [Originally Added On: October 31st, 2012]
- Finding A Cure For Cancer with Dr. Aaron Rapoport - Video [Last Updated On: October 31st, 2012] [Originally Added On: October 31st, 2012]
- First gene therapy to go on sale in Europe in 2013: company [Last Updated On: November 7th, 2012] [Originally Added On: November 7th, 2012]
- Nanomedicine: Infectious Diseases, Immunotherapy, Diagnostics, Antifibrotics, Toxicology And Gene Me - Video [Last Updated On: November 14th, 2012] [Originally Added On: November 14th, 2012]
- Stress gene linked to heart attack – Study [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- Why not gift yourself with gene test this Christmas? [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- "Stress gene" may raise heart attack risk in healthy people [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- 'Stress Gene' Ups Heart Attack, Death Risk [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- Common disorders: It's not the genes themselves, but how they are controlled [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- What is a gene? - Genetics Home Reference [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- Gene Medicine | Business Outline | About Us | TAKARA BIO INC. [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- Gene Therapy Clinical Trials Worldwide [Last Updated On: December 20th, 2013] [Originally Added On: December 20th, 2013]
- Genentech - Official Site [Last Updated On: December 21st, 2013] [Originally Added On: December 21st, 2013]
- Gene Therapy - American Medical Association [Last Updated On: December 23rd, 2013] [Originally Added On: December 23rd, 2013]
- Researchers identify gene that influences the ability to remember faces [Last Updated On: December 24th, 2013] [Originally Added On: December 24th, 2013]
- Gene That Influences Bonding Also Found To Impact Facial Recognition [Last Updated On: December 24th, 2013] [Originally Added On: December 24th, 2013]
- Gene Therapy Method Targets Tumor Blood Vessels [Last Updated On: December 24th, 2013] [Originally Added On: December 24th, 2013]
- Latin Americans inherited diabetes gene risk from Neanderthals [Last Updated On: December 26th, 2013] [Originally Added On: December 26th, 2013]
- Gene that influences the ability to remember faces identified [Last Updated On: December 30th, 2013] [Originally Added On: December 30th, 2013]
- Study supports a causal role in narcolepsy for a common genetic variant [Last Updated On: January 2nd, 2014] [Originally Added On: January 2nd, 2014]
- Increasing Investments in Molecular Biology Research Drives the Market for DNA Gene Chips, According to a New Trend ... [Last Updated On: January 2nd, 2014] [Originally Added On: January 2nd, 2014]
- Loss of Function of a Single Gene Linked to Diabetes in Mice [Last Updated On: January 3rd, 2014] [Originally Added On: January 3rd, 2014]
- Gene Medicine and Health [Last Updated On: January 3rd, 2014] [Originally Added On: January 3rd, 2014]
- Gene Therapy - Nature [Last Updated On: January 5th, 2014] [Originally Added On: January 5th, 2014]
- KidsHealth for Parents - Gene Therapy and Children [Last Updated On: January 5th, 2014] [Originally Added On: January 5th, 2014]
- Gene Patent Case Fuels U.S. Court Test of Stem Cell Right [Last Updated On: January 6th, 2014] [Originally Added On: January 6th, 2014]
- Gene Mutation Increases Certain Health Risks For Blacks, Study Finds [Last Updated On: January 6th, 2014] [Originally Added On: January 6th, 2014]
- Single faulty gene causes major type 2 diabetes symptom in mice [Last Updated On: January 6th, 2014] [Originally Added On: January 6th, 2014]
- No 'brakes' -- Study finds mechanism for increased activity of oncogene in certain cancers [Last Updated On: January 6th, 2014] [Originally Added On: January 6th, 2014]
- AML score that combines genetic and epigenetic changes might help guide therapy [Last Updated On: January 9th, 2014] [Originally Added On: January 9th, 2014]
- Stem cell research identifies new gene targets in patients with Alzheimer's disease [Last Updated On: January 9th, 2014] [Originally Added On: January 9th, 2014]
- 14 new gene targets in Alzheimer’s identified [Last Updated On: January 10th, 2014] [Originally Added On: January 10th, 2014]
- Scientists uncover new target for brain cancer treatment [Last Updated On: January 11th, 2014] [Originally Added On: January 11th, 2014]
- Tweaking MRI to Track Creatine May Spot Heart Problems Earlier, Penn Medicine Study Suggests [Last Updated On: January 13th, 2014] [Originally Added On: January 13th, 2014]
- RSNA: Gene Variation Associated with Brain Atrophy in Mild Cognitive Impairment [Last Updated On: January 14th, 2014] [Originally Added On: January 14th, 2014]
- Keeping Stem Cells Pluripotent [Last Updated On: January 14th, 2014] [Originally Added On: January 14th, 2014]
- Gene variation associated with brain atrophy in mild cognitive impairment [Last Updated On: January 14th, 2014] [Originally Added On: January 14th, 2014]
- Genes: MedlinePlus Medical Encyclopedia - National Library of ... [Last Updated On: January 15th, 2014] [Originally Added On: January 15th, 2014]
- Gene Therapy May Restore Sight in People With Rare Blinding Disease [Last Updated On: January 16th, 2014] [Originally Added On: January 16th, 2014]
- Gene therapy treats blindness [Last Updated On: January 16th, 2014] [Originally Added On: January 16th, 2014]
- New Genetic Clue to Lupus Is Found [Last Updated On: January 17th, 2014] [Originally Added On: January 17th, 2014]
- New Gene Machine Could Mean More Accurate Diagnosis [Last Updated On: January 18th, 2014] [Originally Added On: January 18th, 2014]
- Same cell death pathway involved in three forms of blindness, study finds [Last Updated On: January 18th, 2014] [Originally Added On: January 18th, 2014]