Restoring lost gene activity prevents many disease signs in an animal model of the rare, single-gene neurodevelopmental condition. The UNC Neuroscience Center lab of Ben Philpot, PhD, led this research.
CHAPEL HILL, NC UNC School of Medicine Scientists have shown for the first time that postnatal gene therapy may be able to prevent or reverse many deleterious effects of a rare genetic disorder called Pitt-Hopkins syndrome. This autism spectrum disorder features severe developmental delay, intellectual disability, breathing and movement abnormalities, anxiety, epilepsy, and mild but distinctive facial abnormalities.
The scientists, who report their results in the journal eLife, devised an experimental, gene-therapy-like technique to restore the normal activity of the gene deficient in people with Pitt-Hopkins syndrome. In newborn mice that otherwise model the syndrome, the treatment prevented the emergence of disease signs including anxiety-like behavior, memory problems, and abnormal gene expression patterns in affected brain cells.
This first, proof-of-principle demonstration suggests that restoring normal levels of the Pitt-Hopkins syndrome gene is a viable therapy for Pitt-Hopkins syndrome, which otherwise has no specific treatment, said senior author Ben Philpot, PhD, Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center.
Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt-Hopkins syndrome arises in a child when one copy of the gene TCF4 is missing or mutated, resulting in an insufficient level of TCF4 protein. Typically, this deletion or mutation occurs spontaneously in the parental egg or sperm cell prior to conception, or in the earliest stages of embryonic life following conception.
Only about 500 cases of the syndrome have been reported worldwide since it was first described by Australian researchers in 1978. But no one knows the syndromes true prevalence; some estimates suggest that there could be more than 10,000 cases in the United States alone.
Since TCF4 is a transcription factor gene, a master switch that controls the activities of at least hundreds of other genes, its disruption from the start of development leads to numerous developmental abnormalities. In principle, preventing those abnormalities by restoring normal TCF4 expression as early as possible is the best treatment strategy but it hasnt yet been tested.
Philpots team, led by first author Hyojin (Sally) Kim, PhD, a graduate student in the Philpot lab during the study, developed a mouse model of Pitt-Hopkins syndrome in which the level of the mouse version of TCF4 could be reliably halved. This mouse model showed many typical signs of the disorder. Restoring full activity of the gene from the start of embryonic life fully prevented these signs. The researchers also found evidence in these initial experiments that gene activity needed to be restored in essentially all types of neurons to prevent the emergence of Pitt-Hopkins signs.
The researchers next set up a proof-of-concept experiment modeling a real-world gene therapy strategy. In engineered mice in which roughly half the expression of the mouse version of Tcf4 was switched off, the researchers used a virus-delivered enzyme to switch the missing expression back on again in neurons, just after the mice were born. Analyses of the brains showed this restoration of activity over the next several weeks.
Even though the treated mice had moderately smaller brains and bodies compared to normal mice, they did not develop many of the abnormal behaviors seen in untreated Pitt-Hopkins model mice. The exception was innate nest-building behavior, in which the treated mice seemed abnormal at first, although their abilities were restored to normal within a few weeks.
The treatment at least partly reversed two other abnormalities seen in untreated mice: altered levels of the genes regulated by TCF4 and altered patterns of neuronal activity as measured in electroencephalograph (EEG) recordings.
These findings offer hope that a future gene therapy will provide significant benefits to individuals with Pitt-Hopkins syndrome even when delivered postnatally; it wont require diagnosis and treatment in utero, Kim said.
Philpot and his lab now plan to explore the effectiveness of their strategy when applied to Pitt-Hopkins mice at later stages of life. They also plan to develop an experimental gene therapy in which the human TCF4 gene itself will be delivered by a virus into a Pitt-Hopkins mouse model a therapy that ultimately could be tested in children with Pitt-Hopkins syndrome.
Well be working on a gene therapy, but our results here suggest that there are other TCF4-restoring approaches that could work, including treatments that boost the activity of the remaining, good TCF4 copy, Philpot said.
The research was supported by the Ann D. Bornstein Grant from the Pitt-Hopkins Research Foundation, the National Institute of Neurological Disorders and Stroke (R01NS114086), the Estonian Research Council, and the Orphan Disease Center at the Perelman School of Medicine at the University of Pennsylvania (MDBR-21-105-Pitt Hopkins).
The paper in eLife Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression was written by Hyojin (Sally) Kim, who is now a scientist at Life Edit Therapeutics, Eric Gao, Adam Draper, Noah Berens, Hanna Vihma, Xinyuan Zhang, Alexandra Higashi-Howard, Kimberly Ritola, Jeremy Simon, Andrew Kennedy, and Ben Philpot.
Media contact: Mark Derewicz, 919-923-0959
Read more here:
Gene Therapy Could Treat Pitt-Hopkins Syndrome, Proof-of-Concept Study Suggests | Newsroom - UNC Health and UNC School of Medicine
- More Stem Cells Extracted For Later Use For My MS [Last Updated On: March 14th, 2011] [Originally Added On: March 14th, 2011]
- Macular Degeneration Improved With Stem Cells [Last Updated On: April 2nd, 2011] [Originally Added On: April 2nd, 2011]
- Macular Degeneration Improved With Stem Cells [Last Updated On: April 3rd, 2011] [Originally Added On: April 3rd, 2011]
- Cells That Heal Us From Cradle To Grave: A Quantum Leap in Medical Science [Last Updated On: April 6th, 2011] [Originally Added On: April 6th, 2011]
- Stem Cell Patient Richard H. MS Treatment [Last Updated On: May 20th, 2011] [Originally Added On: May 20th, 2011]
- STEM CELLS FOR MACULAR DEGENERATION Sam Smith's story.wmv [Last Updated On: May 22nd, 2011] [Originally Added On: May 22nd, 2011]
- STEM CELLS FOR MACULAR DEGENERATION Sam Smith's story.wmv [Last Updated On: May 22nd, 2011] [Originally Added On: May 22nd, 2011]
- Dr. Janet Rossant, Premier's Summit Award 2010 recipient [Last Updated On: May 31st, 2011] [Originally Added On: May 31st, 2011]
- Visions Episode 92: Stem Cells Discovery [Last Updated On: May 31st, 2011] [Originally Added On: May 31st, 2011]
- PROSTATE CANCER and stem cells.wmv [Last Updated On: June 9th, 2011] [Originally Added On: June 9th, 2011]
- Stem Cells Used to Grow Windpipes [Last Updated On: June 10th, 2011] [Originally Added On: June 10th, 2011]
- Visions Episode 92: Stem Cells Discovery [Last Updated On: July 12th, 2011] [Originally Added On: July 12th, 2011]
- PROSTATE CANCER and stem cells [Last Updated On: July 16th, 2011] [Originally Added On: July 16th, 2011]
- Doctors Use Stem Cells to Grow New Windpipes [Last Updated On: August 29th, 2011] [Originally Added On: August 29th, 2011]
- Sims 2 Mafia Story Part 7 - Farewell, Godfather/Stem Cell Medicine [Last Updated On: August 30th, 2011] [Originally Added On: August 30th, 2011]
- Regenerative Medicine: Pathways to Cure - Version 2.0 [Last Updated On: September 8th, 2011] [Originally Added On: September 8th, 2011]
- Stem Cell Research: Huntington's Disease [Last Updated On: September 10th, 2011] [Originally Added On: September 10th, 2011]
- Adult Stem Cell Therapy for COPD: One Man's Story [Last Updated On: September 24th, 2011] [Originally Added On: September 24th, 2011]
- Stem Cell Update from Panama 3 Years Later [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- Stem Cell Update from Panama 3 Years Later [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- Regenerative Medicine and Applications of Stem Cell Research [Last Updated On: October 10th, 2011] [Originally Added On: October 10th, 2011]
- Stem Cell Therapy for Sickle Cell Anemia - Video [Last Updated On: October 14th, 2011] [Originally Added On: October 14th, 2011]
- Stem_Cell_Therapy_for_ALS.wmv - Video [Last Updated On: October 17th, 2011] [Originally Added On: October 17th, 2011]
- Spinal Cord Injury: Progress and Promise in Stem Cell Research - Video [Last Updated On: October 18th, 2011] [Originally Added On: October 18th, 2011]
- Stem Cells: The Hope The Hype and the Science - Video [Last Updated On: October 22nd, 2011] [Originally Added On: October 22nd, 2011]
- What are stem cells? How can they be used for medical benefit? - Video [Last Updated On: October 24th, 2011] [Originally Added On: October 24th, 2011]
- What are stem cells? How can they be used for medical benefit? - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- Batten Disease: Spotlight on Stem Cell Research - Stephen Huhn - Video [Last Updated On: October 26th, 2011] [Originally Added On: October 26th, 2011]
- The CIRM Creativity Awards: Training 21st Century Stem Cell Scientists - Video [Last Updated On: October 28th, 2011] [Originally Added On: October 28th, 2011]
- What Organ Shortage? Just Make Your Own! Stem Cells and Organ Engineering - Video [Last Updated On: October 28th, 2011] [Originally Added On: October 28th, 2011]
- StemEnhance is the Biggest Scientific Medical breakthrough of our time - World Exclusive! - Video [Last Updated On: November 9th, 2011] [Originally Added On: November 9th, 2011]
- StemEnhance is the Biggest Scientific Medical breakthrough of our time - World Exclusive! - Video [Last Updated On: November 10th, 2011] [Originally Added On: November 10th, 2011]
- Alumni Profile: Dr. John Tisdale, NIH Researcher, Stem Cell Transplants and Sickle Cell - Video [Last Updated On: November 12th, 2011] [Originally Added On: November 12th, 2011]
- Intel co-founder Andrew Grove gives keynote at 2011 World Stem Cell Summit in Pasadena - Video [Last Updated On: November 16th, 2011] [Originally Added On: November 16th, 2011]
- Austin Forum - Nov 1st (Highlights) - Video [Last Updated On: November 17th, 2011] [Originally Added On: November 17th, 2011]
- Stem Cell Based Therapies for Blindness: David Hinton - CIRM Science Writer's Seminar - Video [Last Updated On: November 18th, 2011] [Originally Added On: November 18th, 2011]
- Dr. Jordan Pomeroy discusses xeno-Free Derivation and Maintenance of Pluripotent Cell Lines - Video [Last Updated On: November 19th, 2011] [Originally Added On: November 19th, 2011]
- So Many Chemicals...So Little Time: Stem Cell Research and Environmental Health - Video [Last Updated On: November 19th, 2011] [Originally Added On: November 19th, 2011]
- Austin Forum - Nov 1st (Part 4 of 4) - Video [Last Updated On: November 23rd, 2011] [Originally Added On: November 23rd, 2011]
- Austin Forum - Nov 1st (Part 2 of 4) - Video [Last Updated On: November 23rd, 2011] [Originally Added On: November 23rd, 2011]
- Austin Forum - Nov 1st (Part 1 of 4) - Video [Last Updated On: November 24th, 2011] [Originally Added On: November 24th, 2011]
- Alan Trounson: Are stem cells the end of disease? - Video [Last Updated On: November 29th, 2011] [Originally Added On: November 29th, 2011]
- Alan Trounson: Are stem cells the end of disease? - Video [Last Updated On: November 29th, 2011] [Originally Added On: November 29th, 2011]
- A4M Stem Cell Fellowship Module II Preview - Video [Last Updated On: December 1st, 2011] [Originally Added On: December 1st, 2011]
- Auxogyn_ASRM_FINAL.mov - Video [Last Updated On: December 2nd, 2011] [Originally Added On: December 2nd, 2011]
- Bruce Lipton,making the connections part 1 - Video [Last Updated On: December 3rd, 2011] [Originally Added On: December 3rd, 2011]
- Assessment of Embryo Viability (Auxogyn_ASRM_First Prize) - Video [Last Updated On: December 4th, 2011] [Originally Added On: December 4th, 2011]
- What is Cord Blood Banking? The Medical Potential of Newborn Stem Cells - Video [Last Updated On: December 7th, 2011] [Originally Added On: December 7th, 2011]
- NAMCP 2011: Ravi Vij, MD, Associate Professor of Medicine, Washington University School of Medicine - Video [Last Updated On: December 9th, 2011] [Originally Added On: December 9th, 2011]
- StemCellTV Talks to Michael Werner of Alliance for Regenerative Medicine at Meeting on the Mesa - Video [Last Updated On: December 9th, 2011] [Originally Added On: December 9th, 2011]
- Future360 - Alan Trounson, CEO of the California Institute of Regenerative Medicine - Video [Last Updated On: December 9th, 2011] [Originally Added On: December 9th, 2011]
- 2011 World Stem Cell Summit Open Comments [Last Updated On: December 11th, 2011] [Originally Added On: December 11th, 2011]
- 2011 Summit: Keynote Address, CIRM's Translational Roadmap to Stem Cell Cures, Alan Trounson, PhD - Video [Last Updated On: December 14th, 2011] [Originally Added On: December 14th, 2011]
- 2011 Summit: Government [Last Updated On: December 14th, 2011] [Originally Added On: December 14th, 2011]
- Autism Stem Cell Trip - Video [Last Updated On: December 17th, 2011] [Originally Added On: December 17th, 2011]
- GeneCell International Dental Pulp Stem Cell's Banking Services - Video [Last Updated On: December 21st, 2011] [Originally Added On: December 21st, 2011]
- GeneCell International Dental Pulp Stem Cell's Banking Services - Video [Last Updated On: December 22nd, 2011] [Originally Added On: December 22nd, 2011]
- Dr Tony Talebi discusses stem cell transplantation in Myeloma with Dr Ratzan - Video [Last Updated On: January 2nd, 2012] [Originally Added On: January 2nd, 2012]
- Craig Venter: Understanding Our Genes - A Step to Personalized Medicine | CIRM Spotlight on Genomics - Video [Last Updated On: January 27th, 2012] [Originally Added On: January 27th, 2012]
- Craig Venter: Understanding Our Genes - A Step to Personalized Medicine | CIRM Spotlight on Genomics - Video [Last Updated On: January 28th, 2012] [Originally Added On: January 28th, 2012]
- Aesthetic Plastic Surgery / Anti Aging Medicine: The Next Generation Symposium Attracts a World Class Faculty to New ... [Last Updated On: January 28th, 2012] [Originally Added On: January 28th, 2012]
- Lecture by stem cell researcher tomorrow [Last Updated On: January 29th, 2012] [Originally Added On: January 29th, 2012]
- Biobanking for Medicine: Technology and Market 2012-2022 [Last Updated On: January 31st, 2012] [Originally Added On: January 31st, 2012]
- 'Personalized medicine' gets $67.5M research boost [Last Updated On: January 31st, 2012] [Originally Added On: January 31st, 2012]
- Clinical Trial for Myelofibrosis that Targets Cancer Stem Cells | CIRM Spotlight on Genomics - Video [Last Updated On: February 1st, 2012] [Originally Added On: February 1st, 2012]
- An Overview of Data Trends in Autologous Stem Cell Research and Clinical Use - James P. Watson, MD - Video [Last Updated On: February 1st, 2012] [Originally Added On: February 1st, 2012]
- An Overview of Data Trends in Autologous Stem Cell Research and Clinical Use - James P. Watson, MD - Video [Last Updated On: February 1st, 2012] [Originally Added On: February 1st, 2012]
- Dr. Ramaswamy on Targeting Dormant Cancer Cells - Video [Last Updated On: February 2nd, 2012] [Originally Added On: February 2nd, 2012]
- Daniel Kraft on Singularity 1 on 1 (part 3) - Video [Last Updated On: February 2nd, 2012] [Originally Added On: February 2nd, 2012]
- Daniel Kraft on Singularity 1 on 1 (part 1) - Video [Last Updated On: February 2nd, 2012] [Originally Added On: February 2nd, 2012]
- Statement - Rx&D Applauds Government of Canada for Investing in Personalized Medicine [Last Updated On: February 3rd, 2012] [Originally Added On: February 3rd, 2012]
- Molecules to Medicine: Plan B: The Tradition of Politics at the FDA [Last Updated On: February 3rd, 2012] [Originally Added On: February 3rd, 2012]
- 'Personalized medicine' gets $67.5M research boost [Last Updated On: February 3rd, 2012] [Originally Added On: February 3rd, 2012]
- The Pet Corner: Behold! The future of modern medicine is here [Last Updated On: February 4th, 2012] [Originally Added On: February 4th, 2012]
- Molecules to Medicine: Plan B: The Tradition of Politics at the FDA [Last Updated On: February 4th, 2012] [Originally Added On: February 4th, 2012]
- Treating Brain Injuries With Stem Cell Transplants - Promising Results [Last Updated On: February 4th, 2012] [Originally Added On: February 4th, 2012]
- Stem Cells to Treat Acne Scarring | Los Angeles | Hollywood | Beverly Hills - Video [Last Updated On: February 6th, 2012] [Originally Added On: February 6th, 2012]
- American CryoStem Completes Cell Processing for Clinical Study [Last Updated On: February 7th, 2012] [Originally Added On: February 7th, 2012]
- IntelliCell Demonstrates at the American Sports Medicine Institute Held in Conjunction with and at the Andrews Sports ... [Last Updated On: February 7th, 2012] [Originally Added On: February 7th, 2012]
- Meet the Founders of Cord Blood Registry - Video [Last Updated On: February 9th, 2012] [Originally Added On: February 9th, 2012]