Children’s Hospital of Philadelphia (CHOP) researchers reported today in the New England Journal of Medicine about a rare but noteworthy outcome in a child treated with an adeno-associated virus (AAV) gene therapy for severe mucopolysaccharidosis type I (MPS I). MPS I, a lysosomal storage disorder also known as Hurler Syndrome, is characterized by an abnormal build-up of various toxic materials, called glycosaminoglycans (GAGs) in the body's cells. Four years after receiving an AAV vector encoding the enzyme α-L-iduronidase (IDUA), a child developed a surgically removable neuroepithelial brain tumor whose cells contained fragments of the therapeutic vector.
Without treatments that alter the disease’s course, children with severe MPS can suffer organ damage, progressive cognitive decline and a substantially reduced life expectancy. The urgent need to improve quality of life and extend lifespans has prompted interest in gene therapies, particularly those using AAV vectors.
“Gene therapy can be lifesaving and transformative for children with devastating disorders,” said Lindsay A. George, MD, the study’s co-senior author, CHOP’s Director of Clinical In Vivo Gene Therapy and an attending physician in the Division of Hematology.
This is the first reported human tumor with molecular evidence that pieces of an AAV gene‑therapy vector inserted into the patient's own DNA were associated with development of a tumor. In this case, the vector's “on switch” (promoter) can activate gene expression in any cell type and was inserted into the PLAG1 gene in brain cells after direct delivery to the central nervous system. The PLAG1 gene is normally active only during early development, and if it becomes switched on at the wrong time, it can promote tumor growth. Laboratory tests of the tumor, including mapping where the vector inserted, measuring gene activity and DNA methylation, supported this link. The tumor was removed, and the child currently demonstrates advanced-for-age neurocognitive function.
In this study, Frederic D. Bushman, PhD, Co-Director of the PennCHOP Microbiome Program and his team at the Perelman School of Medicine, collaborated with Dr. George's laboratory and CHOP researchers to investigate insertion of vector DNA into patient's cells that were associated with development of the tumor.
“This case took persistence and several different approaches to investigate,” said Bushman. “It shows why it’s so important to carefully examine unusual medical findings.”
George said risk of a developing a tumor after AAV gene therapy may depend on multiple factors such as therapeutic design, including the vector promoter and route of delivery, as well as the proliferative state of the cells that received gene therapy DNA and patient history (such as immune status).
“There are several possible factors that may have contributed to this observation, and those factors differ across AAV treatments and patients,” said George. “Because this report describes just one case – and AAV therapies overall have thus far demonstrated excellent long-term safety in more than 6,000 people – it would be premature to generalize this single finding to all other AAV gene therapies.”
She recommended careful assessment of the risks and benefits of the therapy and continued research to better define and minimize integration risk, use of multiple complementary molecular methods to detect integration, and routine long-term surveillance, particularly of the most heavily transduced tissues following AAV administration. CHOP and George’s team continue to study the long-term safety of AAV and are working to advance the safety and efficacy of these transformative therapies.
A Family’s Journey
Adam was born in April of 2020, to Mary Beth and David of New Jersey. From the beginning, his family was thrust into a rare-disease world when newborn screening revealed a severe MPS I diagnosis (Hurler Syndrome). In severe MPS I, characteristic signs such as coarsened facial features, skeletal and spinal deformities, and developmental delays appear within the first 1–2 years and may be accompanied by macrocephaly, corneal clouding, hearing loss, recurrent infections, enlarged organs, heart disease, short stature, hernias, and carpal tunnel.
At six weeks old, Adam began weekly enzyme replacement infusions, and by August 2020 his care team at CHOP recommended a hematopoietic stem cell transplant as the best early chance to preserve his brain. However, by the end of November, it was clear the transplant was failing. Faced with the prospect of a second, more toxic transplant, his family and care team began to weigh alternatives.
In May 2021 at 13 months old, Adam was enrolled in a gene therapy clinical trial at CHOP. The day after dosing, his mother remembers a light coming on in his eyes – an alertness she had not seen before. Over the next months and years, more changes unfolded: a budding love of letters and sign language, reading at three, and by five an insatiable curiosity about the world.
“Thanks to early identification, the subsequent bone marrow transplant and AAV9-IDUA gene therapy treatment, Adam’s cognitive development was preserved, allowing him to perform far above expectations – reading well, loving math, and scoring in the 99th percentile for his age – outcomes that would have been highly unlikely without these interventions,” said Rebecca Ahrens-Nicklas, MD, PhD, a study co-author, pediatric geneticist and Director of CHOP’s Gene Therapy for Inherited Metabolic Disorders Program, who is also Adam’s doctor.
In June 2025, Ahrens-Nicklas discovered a brain lesion, and Adam was immediately admitted to CHOP for surgery to remove it, followed by a second operation in August to excise the remaining portion. The team continues close surveillance, following up with Adam every three months with brain and spine MRIs.
Now six and in kindergarten, Adam brightens every room with his curiosity. He continues to receive ongoing enzyme infusions, regular MRIs, and specialty care for the orthopedic and developmental challenges of MPS I, with future procedures already planned as part of his long‑term management.
“CHOP’s coordinated, multidisciplinary approach – uniting clinicians, translational scientists, surgeons, and geneticists – is essential to ensuring thoughtful treatment decisions, rigorous follow‑up, and clear, responsible communication,” said George. “Our precision care enabled prompt diagnosis and treatment of a rare complication, preserving and advancing this child’s development.”
His mother’s message is simple and urgent: gene therapy gave Adam time and cognitive abilities that have changed their lives, and while safety must be paramount, the option to access transformative treatments matters to families who live every day with the tradeoffs of a rare, progressive disease.
“Knowing what we know now, we would choose gene therapy again,” said Mary Beth. “It gave our son a chance to live, to learn, and to truly thrive. Even facing the hardest moments, watching him laugh, discover, and grow has made the risk worth taking.”
Ahrens-Nicklas et al. “Neuroepithelial Tumor with AAV Integration After ICM Vector Delivery.” NEJM. Online May 13, 2026. DOI: 10.1056/NEJM 2601608.
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Children’s Hospital of Philadelphia (CHOP) researchers reported today in the New England Journal of Medicine about a rare but noteworthy outcome in a child treated with an adeno-associated virus (AAV) gene therapy for severe mucopolysaccharidosis type I (MPS I). MPS I, a lysosomal storage disorder also known as Hurler Syndrome, is characterized by an abnormal build-up of various toxic materials, called glycosaminoglycans (GAGs) in the body's cells. Four years after receiving an AAV vector encoding the enzyme α-L-iduronidase (IDUA), a child developed a surgically removable neuroepithelial brain tumor whose cells contained fragments of the therapeutic vector.
Without treatments that alter the disease’s course, children with severe MPS can suffer organ damage, progressive cognitive decline and a substantially reduced life expectancy. The urgent need to improve quality of life and extend lifespans has prompted interest in gene therapies, particularly those using AAV vectors.
“Gene therapy can be lifesaving and transformative for children with devastating disorders,” said Lindsay A. George, MD, the study’s co-senior author, CHOP’s Director of Clinical In Vivo Gene Therapy and an attending physician in the Division of Hematology.
This is the first reported human tumor with molecular evidence that pieces of an AAV gene‑therapy vector inserted into the patient's own DNA were associated with development of a tumor. In this case, the vector's “on switch” (promoter) can activate gene expression in any cell type and was inserted into the PLAG1 gene in brain cells after direct delivery to the central nervous system. The PLAG1 gene is normally active only during early development, and if it becomes switched on at the wrong time, it can promote tumor growth. Laboratory tests of the tumor, including mapping where the vector inserted, measuring gene activity and DNA methylation, supported this link. The tumor was removed, and the child currently demonstrates advanced-for-age neurocognitive function.
In this study, Frederic D. Bushman, PhD, Co-Director of the PennCHOP Microbiome Program and his team at the Perelman School of Medicine, collaborated with Dr. George's laboratory and CHOP researchers to investigate insertion of vector DNA into patient's cells that were associated with development of the tumor.
“This case took persistence and several different approaches to investigate,” said Bushman. “It shows why it’s so important to carefully examine unusual medical findings.”
George said risk of a developing a tumor after AAV gene therapy may depend on multiple factors such as therapeutic design, including the vector promoter and route of delivery, as well as the proliferative state of the cells that received gene therapy DNA and patient history (such as immune status).
“There are several possible factors that may have contributed to this observation, and those factors differ across AAV treatments and patients,” said George. “Because this report describes just one case – and AAV therapies overall have thus far demonstrated excellent long-term safety in more than 6,000 people – it would be premature to generalize this single finding to all other AAV gene therapies.”
She recommended careful assessment of the risks and benefits of the therapy and continued research to better define and minimize integration risk, use of multiple complementary molecular methods to detect integration, and routine long-term surveillance, particularly of the most heavily transduced tissues following AAV administration. CHOP and George’s team continue to study the long-term safety of AAV and are working to advance the safety and efficacy of these transformative therapies.
A Family’s Journey
Adam was born in April of 2020, to Mary Beth and David of New Jersey. From the beginning, his family was thrust into a rare-disease world when newborn screening revealed a severe MPS I diagnosis (Hurler Syndrome). In severe MPS I, characteristic signs such as coarsened facial features, skeletal and spinal deformities, and developmental delays appear within the first 1–2 years and may be accompanied by macrocephaly, corneal clouding, hearing loss, recurrent infections, enlarged organs, heart disease, short stature, hernias, and carpal tunnel.
At six weeks old, Adam began weekly enzyme replacement infusions, and by August 2020 his care team at CHOP recommended a hematopoietic stem cell transplant as the best early chance to preserve his brain. However, by the end of November, it was clear the transplant was failing. Faced with the prospect of a second, more toxic transplant, his family and care team began to weigh alternatives.
In May 2021 at 13 months old, Adam was enrolled in a gene therapy clinical trial at CHOP. The day after dosing, his mother remembers a light coming on in his eyes – an alertness she had not seen before. Over the next months and years, more changes unfolded: a budding love of letters and sign language, reading at three, and by five an insatiable curiosity about the world.
“Thanks to early identification, the subsequent bone marrow transplant and AAV9-IDUA gene therapy treatment, Adam’s cognitive development was preserved, allowing him to perform far above expectations – reading well, loving math, and scoring in the 99th percentile for his age – outcomes that would have been highly unlikely without these interventions,” said Rebecca Ahrens-Nicklas, MD, PhD, a study co-author, pediatric geneticist and Director of CHOP’s Gene Therapy for Inherited Metabolic Disorders Program, who is also Adam’s doctor.
In June 2025, Ahrens-Nicklas discovered a brain lesion, and Adam was immediately admitted to CHOP for surgery to remove it, followed by a second operation in August to excise the remaining portion. The team continues close surveillance, following up with Adam every three months with brain and spine MRIs.
Now six and in kindergarten, Adam brightens every room with his curiosity. He continues to receive ongoing enzyme infusions, regular MRIs, and specialty care for the orthopedic and developmental challenges of MPS I, with future procedures already planned as part of his long‑term management.
“CHOP’s coordinated, multidisciplinary approach – uniting clinicians, translational scientists, surgeons, and geneticists – is essential to ensuring thoughtful treatment decisions, rigorous follow‑up, and clear, responsible communication,” said George. “Our precision care enabled prompt diagnosis and treatment of a rare complication, preserving and advancing this child’s development.”
His mother’s message is simple and urgent: gene therapy gave Adam time and cognitive abilities that have changed their lives, and while safety must be paramount, the option to access transformative treatments matters to families who live every day with the tradeoffs of a rare, progressive disease.
“Knowing what we know now, we would choose gene therapy again,” said Mary Beth. “It gave our son a chance to live, to learn, and to truly thrive. Even facing the hardest moments, watching him laugh, discover, and grow has made the risk worth taking.”
Ahrens-Nicklas et al. “Neuroepithelial Tumor with AAV Integration After ICM Vector Delivery.” NEJM. Online May 13, 2026. DOI: 10.1056/NEJM 2601608.
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