A Potential Cure for Autism: New Research Finds That Gene Therapy Could Treat Pitt-Hopkins Syndrome

DNA Gene Therapy Concept

A new study has shown that gene therapy may be able to prevent or reverse many deleterious effects of Pitt-Hopkins syndrome

New research from the UNC Neuroscience Center lab of Ben Philpot, Ph.D., finds restoring lost gene activity prevents many disease signs in an animal model of Pitt-Hopkins syndrome, a rare, single-gene neurodevelopmental condition.

Pitt-Hopkins syndrome is a rare genetic condition caused by a mutation in the TCF4 gene on chromosome 18. Pitt-Hopkins syndrome is characterized by developmental delay, potential respiratory concerns such as episodic hyperventilation and/or breath-holding while awake, recurrent seizures/epilepsy, gastrointestinal difficulties, a lack of speech, and distinctive facial features. Children diagnosed with Pitt-Hopkins syndrome often have a happy and lively attitude with frequent smiling and laughing.

The prevalence of Pitt-Hopkins syndrome in the general population is unclear. However, some estimates place the frequency of Pitt-Hopkins syndrome between 1 in 34,000 and 1 in 41,000. The disorder affects both men and women and is not restricted to a single ethnic group.

Pitt Hopkins syndrome is classified as an Autism Spectrum Disorder, and some people who have it have been diagnosed with Autism, ‘atypical’ autistic characteristics, and/or Sensory Integration Dysfunction. Many researchers believe that treating Pitt Hopkins syndrome will lead to treatments for similar disorders because of its genetic link to autism and other conditions.

For the first time, researchers at the University of North Carolina School of Medicine have shown that postnatal gene therapy may be able to prevent or reverse many of the negative effects of Pitt-Hopkins syndrome, a rare genetic disorder. Severe developmental delay, intellectual disability, respiratory and movement abnormalities, anxiety, epilepsy, and moderate but distinctive facial abnormalities are all symptoms of this autism spectrum disorder.

The scientists, who published their findings in the journal eLife, created an experimental, gene-therapy-like technique to restore the normal function of the gene-deficient in people with Pitt-Hopkins syndrome. The medication prevented the onset of disease indicators such as anxiety-like behavior, memory impairments, and abnormal gene expression patterns in afflicted brain cells in newborn mice that would otherwise model the syndrome.

“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, Ph.D., Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the University of North Carolina (UNC) Neuroscience Center.

Brain Protein Cre

Brain section image: protein Cre (green) delivered to cells as gene therapy via AAV. Credit: Philpot Lab (UNC School of Medicine)

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 syndrome’s 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 hasn’t yet been tested.

Philpot’s team, led by first author Hyojin (Sally) Kim, Ph.D., 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 the 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.

Next, the researchers 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 won’t 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.

“We’ll 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).

Reference: “Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression” by Hyojin Kim, Eric B Gao, Adam Draper, Noah C Berens, Hanna Vihma, Xinyuan Zhang, Alexandra Higashi-Howard, Kimberly D Ritola, Jeremy M Simon, Andrew J Kennedy and Benjamin D Philpot, 10 May 2022, eLife.
DOI: 10.7554/eLife.72290

28 Comments on "A Potential Cure for Autism: New Research Finds That Gene Therapy Could Treat Pitt-Hopkins Syndrome"

  1. The cure to autism is food. Remove msg from the diet which resides in 80% of our foods like gluten and casein products.
    Watch unblind my mind from catherine reid on youtube.
    Her talk changed my life for the better.

    • (CITATION NEEDED) | June 8, 2022 at 10:30 pm | Reply

      Yes, Less MSG. That will certainly reverse proven differences in DNA. If I remove MSG form my diet will I just start being “normal”? Do you have ANY studies to prove this? Can you explain to me why this happens? No. No you cannot.

  2. Kaleigh O'Grady | June 5, 2022 at 10:26 am | Reply

    I am really, really tired of seeing studies about “curing” autism. Autism is not a disease or a disorder. It is simply neurodivergency, a different neurotypy, a natural variation within human neurology. As someone who is neurodivergent (both autism and ADHD), I neither want nor need to be “cured”. To suggest that people like me should be “cured” is straight-up eugenics and ableism. And it’s really, really not a good look.

  3. Lol! I wouldn’t want to change my son at all! He was born with autism,the problem is NOT with Autism.The problem is with the “slow-moving evolution” of humans who think that Autism is a “problem”.Autism,ADHD,ADD, Dyslexia, Dyscalculia, Dysgraphia etc. IS evolution in the happening Now!

  4. Lol! I wouldn’t want to change my son at all! He was born with autism,the problem is NOT with Autism.The problem is with the “slow-moving evolution” of humans who think that Autism is a “problem”.Autism,ADHD,ADD, Dyslexia, Dyscalculia, Dysgraphia etc. IS evolution of humans. Autism Is the future. in the happening Now!
    Think about this for a while, ya ‘normal’ idiots!lol

    • Some people with autism are lucky to have a mild condition and being highly functional in our society. But, how about those people with severe conditions that needs to have a quality of life? Think about it.
      If you don’t want your son to be treated, then, that is fine. It’s your choice.

    • You're just a bot. What do you care! | June 18, 2022 at 11:05 am | Reply

      Shove off bot NPC! You only want to payoff your debt slavery considering that woke schools lecture you to oppose actual research! And don’t double post. https://www.youtube.com/watch?v=JOMYsOGei08&t=1s

  5. Food is not a cure for autism. Welcome to the research over the past 20+ years

  6. Actually sick. We need to spend less time searching for a cure and more time implementing accommodations for disabled people, which is actually feasible! Autistic people don’t want to stop being autistic they want to be able to live as they are.

  7. Becca Calloway | June 6, 2022 at 12:13 am | Reply

    This article is not titled correctly. The subtitle about Pitt-Hopkins Syndrome should be the actual title. There are so few cases of the syndrome they are still figuring out how to classify it. It may resemble autism, but that doesn’t make them the same. Many people with autism function quite well. SciTech daily editors need to fix that title.

  8. Thomas Elley | June 6, 2022 at 7:03 am | Reply

    I’m really sickened by your article’s title that suggests we need to “cure” autism. It’s like saying we need to “cure” short people, or people with brown eyes. It’s not a disease or a problem that needs to be “solved”, it’s just a way that people are. To imply that it’s something harmful and detrimental to people’s lives is disgusting. Your article itself says that children with this particular syndrome have a happy and playful disposition – why on earth would you want to change that?

    • Short people still function properly. The autistic brain cannot interpret social signals. Most mass shootings are committed by autistic men. I would say there is something wrong with how their brain is operating.

      • Hello, someone with autism here. Your comment is unbelievably ableist. It is always the able that claim there is something wrong with metal disabilities. It’s always the able to want a cure for a disability they don’t have. Of course there is some autistic people claiming the same here, but they are mainly people that have been mentally brainwashed and beaten down by the able bodied to believe it. Because society cannot accept people who are different.
        For the school shooting part, as far as I know, that is a stereotype. And even if it was true, it does not mean all autistic people are violent. For someone who acts smart, you seem to hold on to backwards and primitive stereotypes and ideas.
        Autism isn’t as terrible as propaganda from Autism Speaks or Next for Autism would tell you. Without my disability, I wouldn’t be me. I wouldn’t get my inspiration from the most unexpected places. I wouldn’t be as funny, creative, sharp, or have any of the ideas I would create. I am proud to be autistic. And seeing ableists like you labeling us as “flawed”, “ill”, “wrong”, or “lesser”, is pretty sad and pathetic to see. And it makes sense, because you’re not capable of perspective.

    • We need a cure. You don’t have to take it. My daughter needs a cure. Please speak for yourself.

  9. Terina Plyler | June 6, 2022 at 7:22 am | Reply

    Autism is not a disease, and us people who are on the spectrum are perplexed why you would want to try to change us. Our brains are wired differently, and if it wasn’t for this difference then humankind would no longer progress in evolution, due to everyone having the same type of brain. Society needs to begin to understand that many high functioning individuals have talents which may contribute to society that cannot be found in a neurotypical mindset. Perhaps learning how to communicate with people who are different, rather than change them to be more like the majority of the population, is the solution?

  10. My son is autistic with ADHD. Autism puts a tremendous stress on his relationships and frequently leaves him feeling isolated. I would use a safe treatment for him in a heartbeat. Talk of discrimination and ableism is utter nonsense. That sort of politically correct foolishness makes as much sense as the body positivity movement shaming people for losing weight and going to the gym.

  11. Elizabeth Hensley | June 6, 2022 at 2:53 pm | Reply

    I have Asperger’s Syndrome. I have challegens but I also have many gifts. I write good poetry, fanfiction and even fiction with my own characters. I am good at Christian web witnessing and know 10 different proofs that God exists. I make my own websites and I spend a lot of time answering questions on Quroa. Please don’t change me. I want to continue to be me.

  12. agree with you completely. I have a severely disabled 20 year old daughter with autism. She’s beautiful, happy, has a wonderful laugh and smile. We take her everywhere with us. But she will never be able to live independently, will never fall in love, get married or have a family of her own. She can’t dial 911 in an emergency or be left home (or anywhere) alone. I would take a cure in a minute. Completely disagree with these people who believe the rest of the world is the problem. And if you have autism and are highly functioning enough to comment on this article, that’s wonderful. My daughter and others with IQs of 40 don’t have that luxury.

    • I agree with you! I’ve always known that my daughter was somewhere on the Autism Spectrum, but after recently hearing about this Pitt- Hopkins Syndrome, I am truly thinking that she may have this. She has bouts of self-injurious behavior as well as severe social issues. I would do almost anything to have a treatment for her.

  13. As an autistic person who wants to be cured, this gives me so much hope!

  14. I’m autistic and I CERTAINLY approve this message! | June 18, 2022 at 11:02 am | Reply

    Reading so many bots in the comes by woksters who merely say what bought and paid for schools tell them to, I’m actually glad to see and article that isn’t written by a gender studies advocate that only writes articles for ad revenue. I can’t stand when “Neurodiversity” groups claim that they speak for people with autism when people like me say otherwise. I don’t need to tell you that people who write articles expressing the opposite of ACTUAL science are nothing more than talking heads without their own opinion. Mind you I have mild autism and I want to leave the spectrum.

  15. To the autistic world who are saying they want to stay autistic that is fine. I am happy you are happy with it. I have a 7 year old son who doesn’t speak can not sit still for a minute gets angry because he can not communicate. I don’t think he is happy about that. So my point is we need a cure or better treatment for autism and if some people want to remain autistic that is their choice but to speak for everyone and say they all are happy with there outcome in life is ridiculous. There is a reason why it’s called the “spectrum” there is a difference in severity in person to person.

  16. I am a 25 year old high functioning autistic and let me say both of you are wrong even if it is evolution we can’t prove it’s in the right direction just like we cannot actually say that autism is a “detriment to society” as each and every one of us is different each are unique and each has our own problems caused by it take me for example I don’t JUST have autism I have schizophrenic disorder I have a iq of 169 and I have depression. You all need to understand it isn’t just the disorder that causes issues it’s also how society and those we care about how makes it difficult… I grew up with my mom and by the time I was 10 I knew I was wrong but no body told me “hey you have autism” or” hey it’s not your fault” no instead they merely laughed and called me stupid as I said some of us don’t need cures we need a helping hand and not all of us need a helping hand but instead we need a cure or even just something to help us focused…but it’s up to us to decide

  17. Some people have severe cases. I stay up at not worrying what will happen to my son when im gone.

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