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Gene therapy n ° 1: Direct gene therapy DDC via viral vector
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare neurodevelopmental disorder characterized by deficient synthesis of dopamine to serotonin. The deficiency affects only 135 children worldwide and is caused by mutations in DOPA decarboxylase (CDD), which leads to a dysfunctional AADC enzyme. It causes physical and developmental problems, including intellectual disability, in at least 70% of patients.
An early-stage clinical trial led by researchers at Wexner Medical Center at Ohio State University and Ohio State University College of Medicine applied direct gene therapy (replacement of genes with functional genes) to seven children aged 4 to 9 years old with AADC deficiency. The results of the study were published in Nature Communication July 12.
The corrected gene (DNA complementary to human AADC; hAADC) was packaged into an adeno-associated virus vector, serotype 2 (AAV2). A direct infusion of AAV2-hAADC was administered to two regions of the midbrain. Dopaminergic neurons from these regions send branching projections to other regions of the brain. Therefore, axonal transport of viral vectors was able to disseminate the therapeutic gene along the brain circuits affected by the gene mutation.
Direct gene therapy was infused into specific regions of the subjects’ brains via an infusion catheter. Next, the researchers used real-time magnetic resonance imaging (MRI) to confirm delivery of the vector.
“Really what we’re doing is putting a different code into the cell,” said Dr. James Elder, director of neurosurgical oncology at the Ohio State Neurological Institute Wexner Medical Center, in a statement. . “And we watch it all happen live. So we keep repeating the MRI and we can see the infusion flourish in the desired nucleus.”
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Dr. James Elder performs gene therapy brain infusion at Ohio State University’s Wexner Medical Center. Image courtesy of Ohio State University Wexner Medical Center.
All seven subjects in the trial exhibited measurable improvements in clinical function and dopamine production, suggesting that restoration of AADC activity in physiological (midbrain) regions may reverse the pathological phenotype seen in the brain. primary deficit in AADC.
“Remarkably, these episodes are the first symptom to go away after gene therapy surgery, and they never come back,” said co-author Dr. Krystof Bankiewicz, PhD, professor of neurological surgery at the Ohio State College of Medicine. “In the months that follow, many patients experience life-changing improvements. Not only do they start to laugh and have a better mood, many are able to start talking and even walking. . “
The team believe that the methodology and results of the trial provide a framework for the treatment of other neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.
Gene therapy n ° 2: Edition of prenatal databases
Hurler’s syndrome, also known as mucopolysaccharidosis type I (MPS-IH), is a lysosomal overload disease that affects approximately one in 100,000 infants worldwide. The disease is caused by a single mutation in the DNA base, where adenine replaces guanine. The disease presents in children under 6 months of age with swelling of the liver and spleen, hernias of the abdominal wall, musculoskeletal abnormalities, retinal and neurocognitive degeneration, and heart disease. If left untreated, patients can die of cardiorespiratory complications before the age of 5 to 10 years.
Current postnatal treatments for children include lifelong immunogenic enzyme replacement therapy and hematopoietic stem cell transplantation. Postnatal systemic gene therapy strategies are also currently under study, but still present inefficiencies and safety concerns. In contrast, the CRISPR base edition may offer a potentially safer and more efficient solution.
Although MPS-IH usually shows symptoms by the age of 6 months, it can be diagnosed before birth. The timing of disease onset suggests that basic in utero editing may provide the opportunity to treat MPS-HI before birth.
With an entirely different approach, researchers at the Children’s Hospital of Philadelphia (CHOP) used a basic DNA editing technique in a prenatal mouse model to correct Hurler’s syndrome. The adenine base editor targeting the guanine-to-adenine mutation in Hurler mice was delivered with an AAV9 in utero. The results of the study were published in Nature Communication July 13.
“This study shows that editing the prenatal basis for Hurler syndrome is feasible in a preclinical mouse model,” said lead author Dr William Peranteau, attending surgeon at CHOP and chair of the department of fetal surgery and pediatric from the university. “In addition to showing the benefit of treating the disease prenatally, we also showed some correction of the disease with a post-birth baseline edit, highlighting the promise of a pre- and postnatal baseline edit for the baby. Hurler syndrome. “
The basic editing strategy has been shown to correct the disease-causing mutation in several disease-affected organs in the mouse model, with high-level correction in the liver and heart. Editing of the prenatal basis was associated with improvement in cardiac and musculoskeletal phenotypes at 6 months of age. Control mice experienced cardiac decline between 4 and 6 months, sometimes resulting in death.
An important advantage of the prenatal baseline edition is the potential immunological benefit of a less immunogenic AAV delivery mechanism. This offers the possibility of administering additional postnatal booster therapy.
The researchers found that mice treated after birth also demonstrated effective target modification in the heart and liver. This highlights the potential benefits of the basic edition as a postnatal treatment; however, the authors noted that the maximum effect can be achieved with earlier treatment.
The authors also noted several areas for improvement before the study results could be clinically translatable. For example, the toxicity of AAV should be carefully evaluated before clinical evaluation, and strategies to improve transduction may improve the efficiency of editing.
“Although the safety of these approaches for mothers and fetuses has yet to be rigorously characterized before clinical translation, this proof of concept study offers hope for genetic diseases with limited postnatal treatments,” said Peranteau.
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