Children’s Hospital of Philadelphia (CHOP) remains on the forefront of investigating the design and delivery of gene therapies to curb and potentially cure congenital diseases. This work is led by pediatric and fetal surgeon William H. Peranteau, MD, Co-Director of CHOP’s Center for Fetal Research and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery.
Dr. Peranteau is a leader of a team awarded a multimillion-dollar National Institutes of Health (NIH) grant to develop gene editing therapies targeting genetic mutations in liver cells for three rare diseases affecting newborns. The team recently announced the development of an ionizable lipid nanoparticle (LNP) to successfully deliver mRNA base-editing tools to the brain. The LNP shows promise in mitigating central nervous system diseases in perinatal mouse models, paving the way for prenatal and postnatal mRNA therapies targeting genetic disorders.
NIH Funding Supports Greater Exploration
A partnership between CHOP and the University of Pennsylvania (Penn) was recently awarded a $26 million grant from the NIH to develop therapies for three rare, incurable genetic diseases impacting newborns in the first weeks and months after birth:
- Phenylketonuria (PKU)
- Hereditary tyrosinemia type 1 (HT1)
- Mucopolysaccharidosis type 1 (MPSI), or Hurler’s syndrome
The most advanced therapies available for each of these disorders have limitations. Previous studies have demonstrated it may be possible to treat these diseases by correcting the disease-causing genetic mutations in patients’ liver cells. Although these diseases impact cells throughout the body, researchers believe correcting the genetic mutation in the liver specifically will be enough to greatly mitigate the effects of the disease, if not cure it.
With this new five-year grant from the NIH, Penn and CHOP researchers will seek to develop and validate the safety of new therapies using CRISPR gene editing tools. The researchers aim to use LNP base editing to develop therapies for both PKU and HT1 and to use adeno associated virus (AAV) base editing to develop a therapy for MPSI.
Discovering a Delivery Strategy
The research team recently announced the identification of an ionizable LNP capable of delivering mRNA base-editing tools to the brain, and they have shown it can mitigate central nervous system (CNS) disease in perinatal mouse models. These findings, published in ACS Nano, open the door to mRNA therapies delivered pre- or postnatally to treat genetic CNS diseases.
Many of these conditions result from a mutation in a single gene, sparking growing interest in using gene editing tools to correct these mutations before birth. However, identifying the appropriate vehicle to deliver these gene editing tools to the CNS and brain has been a challenge. Viral vectors used to deliver gene therapies have some potential drawbacks, including pre-existing viral immunity and vector-related adverse events, and other options like LNPs have not been investigated extensively in the perinatal brain.
The research team screened a library of ionizable LNPs. These are microscopic fat bubbles with a positive charge at low pH but a neutral charge at physiological conditions in the body. After identifying which LNPs were best able to penetrate the blood-brain barrier in fetal and newborn mice, they optimized their top-performing LNP to be able to deliver base-editing tools. The LNPs were then used to deliver mRNA for an adenine base editor, which would correct a disease-causing mutation in the lysosomal storage disease, MPSI, by changing the errant adenine to guanine.
The researchers showed their LNP was able to improve the symptoms of the lysosomal storage disease in the neonatal mouse brain, as well as deliver mRNA base-editing tools to the brain of other animal models. They also showed the LNP was stable in human cerebrospinal fluid and could deliver mRNA base-editing tools to patient-derived brain tissue.
“This proof-of-concept study supports the safety and efficacy of LNPs for the delivery of mRNA-based therapies to the central nervous system,” says Peranteau, co-senior author. “Taken together, these experiments provide the foundation for additional translational studies.”
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Children’s Hospital of Philadelphia (CHOP) remains on the forefront of investigating the design and delivery of gene therapies to curb and potentially cure congenital diseases. This work is led by pediatric and fetal surgeon William H. Peranteau, MD, Co-Director of CHOP’s Center for Fetal Research and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery.
Dr. Peranteau is a leader of a team awarded a multimillion-dollar National Institutes of Health (NIH) grant to develop gene editing therapies targeting genetic mutations in liver cells for three rare diseases affecting newborns. The team recently announced the development of an ionizable lipid nanoparticle (LNP) to successfully deliver mRNA base-editing tools to the brain. The LNP shows promise in mitigating central nervous system diseases in perinatal mouse models, paving the way for prenatal and postnatal mRNA therapies targeting genetic disorders.
NIH Funding Supports Greater Exploration
A partnership between CHOP and the University of Pennsylvania (Penn) was recently awarded a $26 million grant from the NIH to develop therapies for three rare, incurable genetic diseases impacting newborns in the first weeks and months after birth:
- Phenylketonuria (PKU)
- Hereditary tyrosinemia type 1 (HT1)
- Mucopolysaccharidosis type 1 (MPSI), or Hurler’s syndrome
The most advanced therapies available for each of these disorders have limitations. Previous studies have demonstrated it may be possible to treat these diseases by correcting the disease-causing genetic mutations in patients’ liver cells. Although these diseases impact cells throughout the body, researchers believe correcting the genetic mutation in the liver specifically will be enough to greatly mitigate the effects of the disease, if not cure it.
With this new five-year grant from the NIH, Penn and CHOP researchers will seek to develop and validate the safety of new therapies using CRISPR gene editing tools. The researchers aim to use LNP base editing to develop therapies for both PKU and HT1 and to use adeno associated virus (AAV) base editing to develop a therapy for MPSI.
Discovering a Delivery Strategy
The research team recently announced the identification of an ionizable LNP capable of delivering mRNA base-editing tools to the brain, and they have shown it can mitigate central nervous system (CNS) disease in perinatal mouse models. These findings, published in ACS Nano, open the door to mRNA therapies delivered pre- or postnatally to treat genetic CNS diseases.
Many of these conditions result from a mutation in a single gene, sparking growing interest in using gene editing tools to correct these mutations before birth. However, identifying the appropriate vehicle to deliver these gene editing tools to the CNS and brain has been a challenge. Viral vectors used to deliver gene therapies have some potential drawbacks, including pre-existing viral immunity and vector-related adverse events, and other options like LNPs have not been investigated extensively in the perinatal brain.
The research team screened a library of ionizable LNPs. These are microscopic fat bubbles with a positive charge at low pH but a neutral charge at physiological conditions in the body. After identifying which LNPs were best able to penetrate the blood-brain barrier in fetal and newborn mice, they optimized their top-performing LNP to be able to deliver base-editing tools. The LNPs were then used to deliver mRNA for an adenine base editor, which would correct a disease-causing mutation in the lysosomal storage disease, MPSI, by changing the errant adenine to guanine.
The researchers showed their LNP was able to improve the symptoms of the lysosomal storage disease in the neonatal mouse brain, as well as deliver mRNA base-editing tools to the brain of other animal models. They also showed the LNP was stable in human cerebrospinal fluid and could deliver mRNA base-editing tools to patient-derived brain tissue.
“This proof-of-concept study supports the safety and efficacy of LNPs for the delivery of mRNA-based therapies to the central nervous system,” says Peranteau, co-senior author. “Taken together, these experiments provide the foundation for additional translational studies.”
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