Credit: Cleber A. Trujillo, UC San Diego
An international team of scientists, led by University of California San Diego School of Medicine researchers, has created a human stem cell-based model of a rare, but devastating, inherited neurological autoimmune condition called Aicardi-Goutieres Syndrome (AGS). In doing so, the team was able to identify unusual and surprising underlying genetic mechanisms that drive AGS and test strategies to inhibit the condition using existing drugs.
Two repurposed FDA-approved drugs showed measurable effect, rescuing cells from the effects of AGS. The findings point to the promise of future clinical trials and to the utility of creating novel stem cell-based models of human diseases when no other models are available.
Our approach can now be used to investigate other neurological conditions, like autism and schizophrenia and overlapping autoimmune disorders that dysfunction in similar ways, said Alysson Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine.
First described in 1984, AGS typically involves early-onset inflammation affecting the brain, immune system and skin. Its severity depends upon which genes are involved there are six types but usually results in pronounced physiological and psychological consequences, from microcephaly (an abnormally small head) and spasticity to skin and vision problems and joint stiffness, all appearing in the first year of life. The syndrome is progressive, resulting in death or a persistent vegetative state in early childhood. Currently, there is no cure; the only treatments are symptomatic or palliative.
The clinical features of AGS mimic those of viral infections acquired in utero, before birth, with increased levels of inflammatory markers and other signatures of inflammatory response. However, Muotri said there is no link between AGS and exogenous pathogens. Previous research has shown that AGS patients have mutations in genes critical to nucleic acid metabolism in the regulation of cellular immune response, among them a deficiency in an enzyme called TREX1, which helps prevent abnormal DNA from accumulating in cells.
Deeper probing into the pathogenesis of AGS has been difficult because animal models do not accurately mimic the human version of the disease. So Muotri, with colleagues, used embryonic stem cells and induced pluripotent stem cells (iPSCs) derived from AGS patients to create six cellular models of the condition. In the past, Muotris lab has developed similar disease-in-a-dish neuronal models of autism, anorexia nervosa and Williams Syndrome, among other rare genetic neurological conditions.
From the iPSCs, they also created cerebral organoids or mini-brains larger clusters of neurons that organize themselves into a cortical structure, similar to a developing human cerebral cortex.
The researchers found that with TREX1 not functioning normally, all of the cell models displayed excess extra-chromosomal DNA and that a major source of the excess DNA came from LINE1 (L1) retroelements. L1s are repetitive sequences of DNA with the ability to autonomously copy-and-paste themselves within the human genome. In the past, they have been called jumping genes and, because their function within cells is largely unknown, junk DNA.
However the term junk DNA is increasingly becoming a misnomer. In work published in 2005, for example, Muotri and colleagues reported that L1s have a high impact on brain cells compared to other tissues, suggesting an important, if so far mysterious, role in brain development.
Since then, he said, researchers around the world have investigated the role of L1s in creating a genetic mosaicism in the brain. These are ancient, genomic parasites that replicate inside our cells. The majority of the current work is focusing on the impact of this genome mosaicism, but we decided to also look outside of the nucleus. And what we found was a big surprise.
In some of the AGS cell models created by the researchers, toxins from excess DNA built up. Others showed an abnormal immune response, secreting toxins that induced cell death in other cells. The combined effect in organoids was a massive reduction in neuron growth when the opposite should occur. These models seemed to mirror the development and progression of AGS in a developing fetus, said Muotri. It was cell death and reduction when neural development should be rising.
The cell death was trigged by the anti-viral response from the L1 molecules outside the nucleus. We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment, said Charles Thomas, a former graduate student in the Muotri lab and first author of the study. This mechanism seems human-specific. We dont see this in the mouse.
The researchers observed that AGS pathogenesis was similar to a retroviral infection and wondered whether existing HIV antiretroviral drugs might be effective in interfering in L1 replication. Two drugs were tested in the cell models: Stavudine and Lamivudine. Both drugs resulted in reduced L1 and cell toxicity. Cell model growth returned in all cell types and in the complex, differentiated colonies of nerve cells that comprise organoids.
The data supported the idea that HIV drugs could benefit AGS patients, Muotri said. A clinical trial led by study co-author Yanick Crow, MRCP, PhD, at Sorbonne Paris Cite University and the University of Manchester, has already started in Europe.
Muotri said the findings were illuminating and encouraging, providing a platform and impetus for further study of the pathology of neuroinflammation and drug discovery. Its important to note that while this work focused on AGS, nerve cells in schizophrenia show an overabundance of L1 elements and there is an overlap with other autoimmune disorders.
This is a great example of how a fundamental basic research could be rapidly translated into clinics. Are there analogous mechanisms at work in these different diseases? Is this modeling strategy relevant for better understanding and treating them? These are questions we will now pursue.
This article has been republished frommaterialsprovided byUCSD. Note: material may have been edited for length and content. For further information, please contact the cited source.
Reference:
Thomas, C. A., Tejwani, L., Trujillo, C. A., Negraes, P. D., Herai, R. H., Mesci, P., . . . Muotri, A. R. (2017). Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. Cell Stem Cell. doi:10.1016/j.stem.2017.07.009
Link:
Brain-in-a-Dish Models Neuroinflammation - Technology Networks
- Podcast 9 Athens part 3 and news [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Podcast 10 Athens part 4 [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Podcast 11 Athens Part 5 [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 12 Cardiac Nuclear Medicine in the UK [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Podcast 13 Choline PET and prostate cancer [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode14 ED function and Dysponea [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- ep 15 Collimator Choice and Reconstruction algorithm [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 16 Dr Strauss on vulnerable plaque [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode17 Chemical Stress [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 18 Myocardial Perfusion Imaging and Diabetes [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 19 The INSPIRE trial [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- 20 Dual isotope with a difference [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 21 The real effect of stress [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 22 D-SPECT [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 23 VQ Reprise [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 24 Hepatobiliary Nuclear Medicine [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 25 Sleep Apnea [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 26 Imaging Post Traumatic Stress Disorder [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 27 Cardiac Stem Cells [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 28 Molly Supply [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 29 Melanoma therapy interview with Dr Ekaterina Dadachova [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 30 Viral Therapy [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 31 breast radiotherapy using radioisotopes [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 32 news from snm [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 33 EBV Imaging and Therapy [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Episode 34 Dr Lele SNM India 2009 [Last Updated On: December 14th, 2009] [Originally Added On: December 14th, 2009]
- Episode 35 Dr Andrew Scott from the Ludwig institute [Last Updated On: January 10th, 2010] [Originally Added On: January 10th, 2010]
- Episode 36 CardiArc [Last Updated On: February 25th, 2010] [Originally Added On: February 25th, 2010]
- Episode 37 Dr Modder Radiosynoviorthesis (Radiation Synovectomy) [Last Updated On: March 31st, 2010] [Originally Added On: March 31st, 2010]
- Episode 38 Indian Nuclear Medicine With Dr Malhotra and Dr Krishna [Last Updated On: May 28th, 2010] [Originally Added On: May 28th, 2010]
- Episode 39 Prof Ora Israel The Utility of Hybrid Imaging [Last Updated On: July 13th, 2010] [Originally Added On: July 13th, 2010]
- Episode 40 New V/Q SPECT developments [Last Updated On: October 11th, 2010] [Originally Added On: October 11th, 2010]
- Episode 41 scintimun [Last Updated On: February 14th, 2011] [Originally Added On: February 14th, 2011]
- Episode 42 Radio-Isotope Supply into the future [Last Updated On: March 6th, 2011] [Originally Added On: March 6th, 2011]
- Podcast 4: DNA therapy [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Sorry about the delay a new podcast will be out soon! [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Podcast 5 Flash 3D [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Podcast 6 Affibody [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Podcast 7 EANM 2006 Athens Part 1 [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Podcast 8 Athens Part 2 [Last Updated On: April 24th, 2011] [Originally Added On: April 24th, 2011]
- Episode 43 Rapidscan Part 1, 720P high quality video version [Last Updated On: May 1st, 2011] [Originally Added On: May 1st, 2011]
- Episode 43 Rapidscan Part 1, Ipod quality video [Last Updated On: May 1st, 2011] [Originally Added On: May 1st, 2011]
- Episode 43 Rapidscan Part 1, Audio version [Last Updated On: May 1st, 2011] [Originally Added On: May 1st, 2011]
- Episode 45 Mummies with cardiovascular disease video [Last Updated On: May 21st, 2011] [Originally Added On: May 21st, 2011]
- Episode 45 Mummies with cardiovascular disease audio edition [Last Updated On: May 21st, 2011] [Originally Added On: May 21st, 2011]
- Episode 46 Dr Gordon DePuey Choosing Reconstruction clinical perspective [Last Updated On: August 7th, 2011] [Originally Added On: August 7th, 2011]
- Episode 46 Dr Gordon DePuey Choosing Reconstruction clinical perspective audio version [Last Updated On: August 7th, 2011] [Originally Added On: August 7th, 2011]
- Episode 47 Cardiac Image Fusion With Dr Kaufmann [Last Updated On: September 18th, 2011] [Originally Added On: September 18th, 2011]
- Episode 47 Cardiac Fusion with Dr Kaufmann video version [Last Updated On: September 18th, 2011] [Originally Added On: September 18th, 2011]
- Dear Steve, I am and many more like me are your one more thing. [Last Updated On: October 9th, 2011] [Originally Added On: October 9th, 2011]
- EPISODE 48 PET MRI camera from Siemens with Dr Georgi audio [Last Updated On: October 23rd, 2011] [Originally Added On: October 23rd, 2011]
- EPISODE 48 PET MRI camera from Siemens Dr Georgi video [Last Updated On: October 23rd, 2011] [Originally Added On: October 23rd, 2011]
- Silicon Biosystems to Present Single-Circulating Tumor Cell Molecular Characterization at the Fourth World CTC Summit [Last Updated On: April 25th, 2012] [Originally Added On: April 25th, 2012]
- Leukaemia cells have a remembrance of things past [Last Updated On: April 25th, 2012] [Originally Added On: April 25th, 2012]
- Technologist Education Requirements Can Help Cut Repeat Scans [Last Updated On: April 25th, 2012] [Originally Added On: April 25th, 2012]
- HKU Collaborative Research Discovers A Novel Molecular Mechanism Of A New Anti-HIV-1 Drug Candidate [Last Updated On: April 25th, 2012] [Originally Added On: April 25th, 2012]
- Focal Segmental Glomerulosclerosis and the Nephrotic Syndrome - Part 1 Clinical - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Electro-Medicine : Biological Physics - The Molecular Basis of Alzheimers Disease - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- osdd heterocyclic compounds and molecular medicines - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Molecule to Medicine: The Biomarker Frontier - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Fulfilling the Promise of Molecular Medicine in a Developmental Brain Disorder - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Focus on Stefanie Dimmeler - Video [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Dundee [Last Updated On: May 4th, 2012] [Originally Added On: May 4th, 2012]
- Nanotechnology In Medicine: Huge Potential, But What Are The Risks? [Last Updated On: May 5th, 2012] [Originally Added On: May 5th, 2012]
- Cutting Edge Technology Coming To DMH [Last Updated On: May 5th, 2012] [Originally Added On: May 5th, 2012]
- This Week in Experimental and Molecular Pathology [Last Updated On: May 5th, 2012] [Originally Added On: May 5th, 2012]
- Researchers' discovery offers hope for cancer, heart disease miracle drugs [Last Updated On: May 7th, 2012] [Originally Added On: May 7th, 2012]
- Penn State student Zachary Hostetler from Garnet Valley is being honored as a student marshal [Last Updated On: May 7th, 2012] [Originally Added On: May 7th, 2012]
- NCKU Student Wins Prestigious Award for Anti-Cancer Research [Last Updated On: May 10th, 2012] [Originally Added On: May 10th, 2012]
- In-Vitro Diagnostics (IVD) Market (Clinical Chemistry, Immunoassays, Molecular Diagnostics, Hematology Analyzers ... [Last Updated On: May 10th, 2012] [Originally Added On: May 10th, 2012]
- Pitt team uses genomics to identify a molecular-based treatment for a viral skin cancer [Last Updated On: May 10th, 2012] [Originally Added On: May 10th, 2012]
- Genomics used to identify a molecular-based treatment for a viral skin cancer [Last Updated On: May 10th, 2012] [Originally Added On: May 10th, 2012]
- 2 molecular biologists get $500K medical prize [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- 2 molecular biologists share $500K medical prize [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- Lab21 Unveils New Molecular Analysis Services at Greenville Site [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- 2 molecular biologists from NYC to share $500K medical prize for pioneering research on cells [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- Two Molecular Biologists Get $500K Medical Prize [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- Pair of molecular biologists receive Albany Medical Center Prize [Last Updated On: May 13th, 2012] [Originally Added On: May 13th, 2012]
- CNIO scientists successfully test the first gene therapy against aging-associated decline [Last Updated On: May 16th, 2012] [Originally Added On: May 16th, 2012]
- Cancer Institute of New Jersey Aims to Advance Personalized Cancer Treatments Through 'Precision Medicine' [Last Updated On: May 16th, 2012] [Originally Added On: May 16th, 2012]