Author: delta

When Rylae-Ann Poulin was a year old, she didn’t crawl or babble like other kids her age. A rare genetic disorder kept her from even lifting her head. Her parents took turns holding her upright at night just so she could breathe comfortably and sleep.

Then, months later. doctors delivered gene therapy directly to her brain.

Now the 4-year-old is walking, running, swimming, reading and riding horses — “just doing so many amazing things that doctors once said were impossible,” said her mother, Judy Wei.

Rylae-Ann, who lives with her family in Bangkok, was among the first to benefit from a new way of delivering gene therapy — attacking diseases inside the brain — that experts believe holds great promise for treating a host of brain disorders.

Her treatment recently became the first brain-delivered gene therapy after its approval in Europe and the United Kingdom for AADC deficiency, a disorder that interferes with the way cells in the nervous system communicate. New Jersey drugmaker PTC Therapeutics plans to seek U.S. approval this year.

Meanwhile, about 30 U.S. studies testing gene therapy to the brain for various disorders are ongoing, according to the National Institutes of Health. One, led by Dr. Krystof Bankiewicz at Ohio State University, also targets AADC deficiency. Others test treatments for disorders such as Alzheimer’s, Parkinson’s and Huntington’s.

Challenges remain, especially with diseases caused by more than a single gene. But scientists say the evidence supporting this approach is mounting — opening a new frontier in the fight against disorders afflicting our most complex and mysterious organ.

“There’s a lot of exciting times ahead of us,” said Bankiewicz, a neurosurgeon. “We’re seeing some breakthroughs.”

The most dramatic of those breakthroughs involve Rylae-Ann’s disease, which is caused by mutations in a gene needed for an enzyme that helps make neurotransmitters like dopamine and serotonin, the body’s chemical messengers. The one-time treatment delivers a working version of the gene.

At around 3 months old, Rylae-Ann began having spells her parents thought were seizures — her eyes would roll back and her muscles would tense. Fluid sometimes got into her lungs after feedings, sending her to the emergency room. Doctors thought she might have epilepsy or cerebral palsy.

Around that time, Wei’s brother sent her a Facebook post about a child in Taiwan with AADC deficiency. The extremely rare disorder afflicts about 135 children worldwide, many in that country. Wei, who was born in Taiwan, and her husband, Richard Poulin III, sought out a doctor there who correctly diagnosed Rylae-Ann. They learned she could qualify for a gene therapy clinical trial in Taiwan.

Though they were nervous about the prospect of brain surgery, they realized she likely wouldn’t live past 4 years old without it.

Rylae-Ann had the treatment at 18 months old on November 13, 2019 — which her parents have dubbed her “reborn day.” Doctors delivered it during minimally invasive surgery, with a thin tube through a hole in the skull. A harmless virus carried in a functioning version of the gene.

“It gets put into the brain cells and then the brain cells make the (neurotransmitter) dopamine,” said Stuart Peltz, CEO of PTC Therapeutics.

Company officials said all patients in their clinical trials showed motor and cognitive improvements. Some of them, Peltz said, could eventually stand and walk, and continue getting better over time.

Bankiewicz said all 40 or so patients in his team’s NIH-funded study also saw significant improvements. His surgical approach is more involved and delivers the treatment to a different part of the brain. It targets relevant circuits in the brain, Bankiewicz said, like planting seeds that cause ivy to sprout and spread.

“It’s really amazing work,” said Jill Morris, a program director with the National Institute of Neurological Disorders and Stroke, which helped pay for the research. “And he has seen a lot of consistency between patients.”

One is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian got gene therapy in 2019, shortly before her 5th birthday. Two months later, she held her head up for the first time. She soon started using her hands and reaching for hugs. Seven months after surgery, she sat up on her own.

“When the world was crumbling around us with COVID, we were at our house celebrating like it was the biggest party of our lives because Rian was just crushing so many milestones that were impossible for so long,” said her mom, Shillann Rodriguez-Pena. “It’s a completely different life now.”

Scientists say there are challenges to overcome before this approach becomes widespread for more common brain diseases.

For example, the timing of treatment is an issue. Generally, earlier in life is better because diseases can cause a cascade of problems over the years. Also, disorders with more complex causes — like Alzheimer’s — are tougher to treat with gene therapy.

“When you’re correcting one gene, you know exactly where the target is,” said Morris.

Ryan Gilbert, a biomedical engineer at New York’s Rensselaer Polytechnic Institute, said there can also be issues with the gene-carrying virus, which can potentially insert genetic information in an indiscriminate way. Gilbert and other researchers are working on other delivery methods, such as messenger RNA – the technology used in many COVID-19 vaccines – to deliver a genetic payload to the nucleus of cells.

Scientists are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But that requires getting around the blood-brain barrier, an inherent roadblock designed to keep viruses and other germs that may be circulating in the bloodstream out of the brain.

A more practical hurdle is cost. The price of gene therapies, borne mostly by insurers and governments, can run into the millions. The one-time PTC therapy, called Upstaza, costs more than $3 million in Europe, for example.

But drugmakers say they are committed to ensuring people get the treatments they need. And researchers are confident they can overcome the remaining scientific obstacles to this approach.

“So I would say gene therapy can be leveraged for many sorts of brain diseases and disorders,” Gilbert said. “In the future, you’re going to see more technology doing these kinds of things.”

The families of Rylae-Ann and Rian said they hope other families dealing with devastating genetic diseases will someday get to see the transformations they’ve seen. Both girls are continuing to improve. Rian is playing, eating all sorts of foods, learning to walk and working on language. Rylae-Ann is in preschool, has started a ballet class, and is reading at a kindergarten level.

When her dad picks her up, “she runs to me … just gives me a hug and says, ‘I love you, Daddy.’ he said. “It’s like it’s a normal day, and that’s all we ever wanted as parents.”

A Russian military plane crash near Tetiana Zamorska’s home in Kyiv, Ukraine, was a sign that it was time for her and her family to leave.

The treacherous, 34-hour pilgrimage that ultimately brought the group of eight by car to temporary accommodations in neighboring Poland last month was physically and emotionally difficult, Zamorska recently told BioNews, Inc., the publisher of this website. The journey and transition have been especially challenging for her son Andrii, who has epidermolysis bullosa (EB) and is mostly bedridden because of his fragile, blistering skin.

Patients with EB need boxes of backup bandages to treat wounds, heaters to stay warm because of thin skin, and a blender to soften food because of scarring in the mouth and esophagus. Zamorska said that 24/7 care is needed for people with more aggressive forms of EB, such as 19-year-old Andrii, who has severe generalized recessive dystrophic EB.

Read more at: https://musculardystrophynews.com/2022/04/29/organizations-helping-rare-disease-patients-ukraine-war-refugees/

Five-year-old Boston Yannotti’s ear-to-ear smile masks what has been an extremely difficult childhood. The young boy, with reddish-brown hair and bright blue eyes like his mother, has been confined within the walls of his house for much of his life, unable to experience the world around him. A trip to the beach or the playground is all but impossible. In fact, simply holding his head up is a herculean task.

That’s because Boston suffers from an ultra-rare disease called AADC deficiency — a genetic disease that stops his brain from producing serotonin and dopamine, a chemical that moves electric signals through the brain and, in turn, controls bodily movement. “He’s been a prisoner in his own body,” his father, Michael Yannotti, said from their home near the Dan River in Eden, a small town around 100 miles northwest of Raleigh. “But he’s the strongest little fighter and still has the biggest smile you will ever see.”

Without the ability to produce dopamine, Boston can’t feed himself, sit upright or communicate. He’s prone to fits of oculogyric crises, which send his eyes upward and his muscles into painful spasms for hours. His small body, pale from a lack of sunlight, is stiff from a lack of use.

His parents, Michael, 26, and Claudia Moore, 25, live in constant fear of him catching a cold, flu or COVID-19 because he struggles to clear his lungs of liquid.

But that could all be about to change. In January, Boston received an experimental gene-therapy for children with AADC deficiency. If successful, his parents and scientists hope, Boston could begin to take control of his body for the first time. The two-way communication between the brain and the body could begin to work.

Read more at: https://www.newsobserver.com/news/local/article258983083.html#storylink=cpy

Madrid, February, 2021.- A new treatment for the rare and fatal neurodegenerative disease Niemann Pick C is closer. University College London (UCL) has just started a preclinical study that will make it possible in the future to apply gene therapy to patients in a clinical trial. This project is done in collaboration with the Columbus Foundation (FC)/Columbus Children’s Foundation (CCF), Viralgen Vector Core and UK MRC (UK Medical Research Council)

Niemann Pick disease type C (NP-C) is an inherited lysosomal storage disorder, in which the systemic accumulation of intracellular lipids leads to a progressive and fatal disorder. “It is an inherited disease caused by a defect in the proteins that transport cholesterol. This defect is caused in 95% of cases by mutations in the NPC1 gene, resulting in accumulation of cholesterol and other fats in the liver, spleen or lungs. Neurological symptoms such as clumsiness in walking, difficulties in swallowing and eating, usually appear later in disease “, explains the president of the Columbus Foundation, Damià Tormo.

Healing through gene therapy: replacing the faulty gene

Frequently this pathology manifests itself in an early age and affects one in every 100,000 people. It is a rare disease for which there is little research in the world. One research group is at University College London (UCL), led by Prof. Ahad Rahim. So far, studies in Prof. Rahim’s laboratory, applying adeno-associated virus (AAV) –mediated gene therapy as a vector carrying the correct gene have shown therapeutic benefit in preclinical studies. “Currently there are no good treatments for this disease and the premature death in these children makes it necessary to find an effective treatment urgently. Prof. Rahim’s group has shown that gene therapy can be a way of hope for these patients and our challenge is to help this research until a treatment is achieved,” adds Tormo.

AAV-mediated gene therapy has great potential to treat NP-C by preventing or slowing neurodegeneration and subsequent fatal neurological disease. “During previous studies in animals, we have shown that direct administration to the brain of an AAV9 vector expressing the human NPC1 gene in neurons has allowed the long-term prevention of neurological symptoms accompanied by the prolongation of the animal’s life. With this new phase of research, we want to improve therapeutic efficacy and move towards the preparation for clinical trials in patients “, explains Prof. Ahad Rahim. “Our challenge is to bring this new gene therapy to Niemann-Pick type C1 (NPC1) patients within a few years“, he concludes.

Viral vectors created in Spain

For the manufacture of the treatment, UCL has FC/CCF as an ally and the support for years from the Association Niemann-Pick Fuenlabrada. Funding for these new activities to be carried out took place around an initiative called “Marta’s trip”. Marta is a girl affected by NPC and her family promoted an activity together with the FC/CCF that managed to raise enough money to undertake this project. In this way, the Foundation will have access to the production of viral vectors and also funding from the UK MRC to help carry out toxicology studies, which represents an important boost to the work plan of Prof. Rahim’s team. The gene therapy vector will be manufactured at Viralgen Vector Core, which is one of the world’s leading companies in the manufacture of viral vectors domiciled in San Sebastián, thanks to the agreement that the Foundation has with this company. Under this agreement, Viralgen provides its knowledge, access to capacity and manufacturing of AAV vectors at a significant discount for clinical programs in rare diseases for which there is limited commercial therapeutic availability. “This contribution of material by FC/CCF and Viralgen is a key and necessary advance to be able to bring the drug to our children since it is one of the great bottlenecks in this project“, comments Marta’s father, Ignacio de la Serna.

Partnerships to develop drugs against rare diseases

FC and their US based sister foundation, CCF, have already made important advances to accelerate other treatments for rare diseases with gene therapy, such as L-amino acid aromatic decarboxylase deficiency (AADC deficiency) or infantile Parkinson’s disease. To date, more than 25 children from around the world have received treatment in the centers in Europe and the US with excellent results that have radically improved their quality of life and that of their families. In addition, the organization has already sealed several alliances with other associations with the aim of promoting internal research programs that currently exist for rare diseases and providing therapeutic access to affected people. For example, we have developed exciting partnerships with the American NGO Cure Rare Disease, the Canadian NGO CureSPG50, and the New York-based biotech company Phoenix Nest to address Sanfilippo type C disease, among others.

The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomized controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation.

TORONTO — A new gene therapy for an extremely rare disorder has offered two Canadian children a new chance at life, allowing them to move on their own after years of being trapped within their own bodies.
The disease is called AAV deficiency, and known more commonly as ‘pediatric Parkinson’s’. It’s a debilitating genetic disorder that effectively cuts off communication between cells in the nervous system, affecting movement

.
For Rian, a little girl from Toronto, this meant that at four years old, her body was still like a newborn’s — she couldn’t support her own head, eat on her own, or play the way other children could.
“She had absolutely no functional, purposeful movement,” Rian’s mother, Shillann Rodriguez-Pena, told CTV News. “It essentially was like her body was a prison that she was trapped in. And we could see the sparkle in her eye, we could always see that she was in there and the desperation of trying to get her out, and how to help her out — it was torturous, truthfully.”

Those who have pediatric Parkinson’s also suffer from episodes called oculogyric crises (OGC), in which they experience muscle spasms, uncontrollable rolling of the eyes, agitation and even pain.
In a post on her Facebook documenting Rian’s journey battling this disease, Rodriguez-Pena wrote that Rian suffered from OGCs every three to four days, and that her episodes lasted up to eight hours.
Rodriguez-Pena told CTV News that it was hard to see her daughter suffer.
“She was going through panic attacks and just the sheer frustration of wanting to
do something and her body not allowing her to,” she said. “Because cognitively, she understands so much.”
Historically, there has been no treatment, just disability and an early death, with the disease often proving fatal.

But in September of 2019, Rian became one of the first recipients of an experimental gene therapy. And within weeks of treatment, she began to move. First it was just her head. Then she could hold objects. Now, at six years old, she can sit on her own. And her mother is blown away. “It really is modern day miracle stuff,” she said. “It really is. The science is absolutely miraculous. “We prayed for years […] to be able to see it for our girl, and it’s incredible.”

In a recent video of Rian’s progress, posted in January, she opens a cupboard door on her own while sitting on the floor in her family’s kitchen. Smiling and laughing, she spins around and reopens the cupboard a few times while her mother, filming, narrates. “New skill alert!” her mother praises her in the video. “Are you so proud you figured that out?”

And after the treatment, those paralyzing seizures never returned. It’s incredible progress, according to Dr. Saadet Andrews, one of many doctors who used to treat Rian in the early years of her life, when she was in and out of the hospital constantly.

“The improvements since the gene therapy is amazing,” he said. “She keeps improving very quickly. To give you an example, from […] nine months to almost four years of age, she didn’t do anything. And from a few months of the gene therapy, she just started holding her head and then started slowly sitting up to show us some great improvements.”

How the new gene therapy works is that the genes needed to restore movement are actually put into AAV viruses, and then injected deep into the brain. Once there, the DNA is taken up by cells, and starts correcting the defect.

The therapy is so new that only 23 children worldwide have received this treatment. All of them were treated by Dr. Krystof Baniewicz, one of the world’s leading experts in pediatric Parkinson’s.
“I never expected this to be to be as significant as what we are seeing,” Bankiewicz told CTV News.
Bankiewicz is a professor and the director of the Brain Health and Performance Center at the Ohio State University College of Medicine. He described the first ideas that would eventually become this gene therapy in a paper 25 years ago.

“[I’ve] devoted decades of my life to develop this technology and [I’m] very, very pleased that they can change people’s lives,” he said.

“Without the gene therapy, they would have never been able to achieve the milestones which they have had so far.”

One of the big positives it that so far, it appears that only one treatment is necessary.
“It’s a one-time treatment, as far as I can tell,” Bankiewicz said. “No one has plateaued, they keep on improving.”

Rian isn’t the only Canadian to have benefitted from this new therapy. A seven-year-old in Vancouver, B.C., is now learning to walk after her life-changing treatment.
Jasmine suffered from OGC up to three times a week before her surgery, her parents told CTV News in an email.

“Our life was dark,” her father, Seila Hok wrote, adding that he had no time to think of his own health, only his daughter’s. He and his wife would take turns to sleep at night so that one of them could keep an eye on Jasmine and make sure she was okay. They suffered abusive comments from their community for having “a kid like Jasmine,” which was heartbreaking for them.

The family was able to send Jasmine to receive the new gene therapy in Ohio as part of a clinical trial funded by the lab.

It’s been 18 months since she received the therapy, and Jasmine is “a different Jasmine,” according to her family.

“She is happier, healthier,” Hok said, adding that she no longer suffers from OGCs, and is able to sit, roll around and eat.

A recent video of Jasmine shows her sitting on an exercise ball on her own, smiling, and vocalizing and grabbing a toy.

In another video sent by the family, she is being trained to walk.

Dr. Bankiewicz is awaiting publication of his preliminary study in the coming weeks.
But although this new therapy is extremely promising, there are still numerous barriers to delivering this care, one of them being cost. Therapies for rare diseases aren’t profitable, so all this is funded by donations, fund raising and charities, with many other children waiting for treatment.

Rian received her gene therapy not in the U.S., but in Poland, where Bankiewicz — who is originally from Poland — was offering surgeries as part of “compassionate use” clinical trials for those who could not wait for the therapy to be offered in the U.S.

“Although it was a risky surgery — it was an eight and a half hour brain surgery in
a foreign country — the risks associated to not having the surgery were far more terrifying,” Rodriguez-Pena said.

She added that it cost the family 45,000 euros — just under $68,000 — to make the trip for the treatment which Dr. Banks says was done not for profit. Some of it was their own savings, while some was raised through websites like GoFundMe.

“And that’s actually quite a modest price,” she said. “Because when you look at other rare diseases such as [spinal muscular atrophy], the price point is astronomically larger.”

Some charities, such as the Columbus Children’s Foundation (CCF), help families battling rare diseases to gain access to new treatments like this one. AAV deficiency is one of the ultra-rare diseases that CCF is trying to help cure by supporting new therapies.

“We want to make sure that what happen to Jasmine and Rian happens for other children,” Laura Hameed, executive director of CCF, told CTV News in a phone call.

“These therapies are clinically promising, but don’t get the interest of the biotech industry because they are too small, so non-profit is the best way to make sure they are advanced.”

Another barrier is that so few people are aware of these type of diseases. And that’s one reason that families like Jasmine and Rian’s are coming forward to share their stories.

“There’s only 130 kids approximately in the world with our disease,” Rodriguez-Pena said. “And the fact that there was a treatment that could so drastically change [Rian’s] quality of life — I feel like there’s a lot of value in sharing that story.”

“There are still so many kids with AAV disease [who] need to get surgery,” Hok said, adding that the most important thing is for others to learn about this disease and about the new gene therapy that can turn things around.

These families have had their childrens’ lives transformed for the better — and now they’re hoping to help others transform young lives too.

“I think gene therapy as a technology and medical procedure is gaining [a] tremendous amount of acceptance right now, and I think success is being seen in multiple diseases,” Bankiewicz said. “There are also other disorders outside of the brain which could benefit from this technology.”

He’s already working on trying to apply this gene therapy to adults with Parkinsons, and hopes that they can expand the current gene therapy to additional sites, so more children can be helped.

Rodriguez-Pena said that the family thinks of Rian’s surgery day as almost a second birthday.
“It’s as if she was reborn in so many ways,” she said.

After she was treated, Rian got a puppy, who happened to be born on the same day that she had her surgery.

So what is the puppy’s name? “Banks”, of course, after the doctor who performed the miracle procedure.