The ICNA along with the global child neurology community mourns the passing of Professor Robert S. Rust, MD.
A towering figure in pediatric neurology, Dr. Rust was a true Renaissance man—a historian, physician, educator, mentor, scientist, ethicist, archivist, and humanitarian. His unparalleled contributions, intellectual brilliance, and compassionate nature have left an indelible legacy on the field of child neurology and the countless lives he touched. Dr Rust passed away on December 22, 2024 at his home in Virginia.
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November 19, 2024
The U.S. Food and Drug Administration (FDA) has granted fast-track approval to Kebilidi (Eladocagene exuparvovec), the first gene therapy in the United States administered via direct intracerebral injection. This approval represents a significant advance in the treatment landscape for aromatic L-amino acid decarboxylase (AADC) deficiency, a rare and debilitating neurogenetic disorder.
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Read more: FDA Approves First-Ever Brain-Injected Gene Therapy for AADC Deficiency
Neurological disorders cause significant morbidity and mortality in children. However, cutting-edge in-utero therapies are transforming the management of these conditions, offering the potential to intervene before birth. Conditions such as spina bifida and genetic disorders like Pompe’s disease are at the forefront of this new frontier.
Spina bifida, a condition where the spinal cord fails to close properly, traditionally requires postnatal surgery. The CuRe Trial, led by Dr. Diana Lee Farmer at UC Davis, is pioneering in-utero treatment using mesenchymal stromal cells derived from the mother’s placenta. This groundbreaking approach aims not only to repair the spinal defect but also to reverse damage before birth. Early results in animals and humans are promising, with treated infants showing normal mobility at birth.
In a parallel development, fetal therapies for genetic disorders like Pompe’s disease are also progressing. Pompe’s is typically treated postnatally with enzyme replacement therapy (ERT), but recent breakthroughs have allowed treatment to begin in the womb. At The Ottawa Hospital, a fetus diagnosed with Pompe’s received ERT via the umbilical vein. The child, born healthy, is now a thriving toddler, showcasing the potential of prenatal interventions to alter disease trajectories.
These in-utero therapies are not limited to spina bifida and Pompe’s disease. Clinical trials are now underway for other genetic conditions, including Neuronopathic Gaucher disease and Mucopolysaccharidosis. As researchers refine these therapies, they are also exploring gene-editing technologies like CRISPR, which could further expand the scope of prenatal treatments.
However, in-utero therapies carry risks for both the mother and the fetus, and long-term safety data are still needed. Ethical considerations, especially concerning gene-editing, also require careful scrutiny. Despite these challenges, these therapies hold immense promise for reducing childhood disabilities and improving outcomes.
As research continues, in-utero treatments may soon become a standard part of prenatal care, offering a future where neurological and genetic conditions can be addressed before birth, changing the lives of countless children and their families.
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Lenmeldy (atidarsagene autotemcel) has received approval from the U.S. Food and Drug Administration. This marks a significant milestone as it is the first gene therapy to be approved by the FDA for the treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile metachromatic leukodystrophy (MLD).
Metachromatic leukodystrophy a debilitating rare condition arises due to a lack of an enzyme known as arylsulfatase A (ARSA), resulting in an accumulation of sulfatides (fatty substances) within the cells. The accumulation of this substance results in damage to both the central and peripheral nervous systems, resulting in the decline of motor and cognitive abilities and ultimately premature mortality. Approximately one in every 40,000 individuals in the United States is affected by MLD. Unfortunately, MLD does not currently have a cure. The main approach to treatment involves providing support and managing symptoms.
Lenmeldy is a unique treatment that involves a personalized infusion of the patient's own hematopoietic (blood) stem cells. These cells have been genetically modified to include functional copies of the ARSA gene. The stem cells are obtained from the patient and modified by incorporating a functional copy of the ARSA gene. The modified stem cells are transplanted back into the patient, where they attach and multiply within the bone marrow. The modified stem cells provide the body with myeloid (immune) cells that generate the ARSA enzyme, aiding in the breakdown of sulfatides and potentially halting the advancement of MLD. Before treatment, patients are required to undergo high-dose chemotherapy, which involves the removal of cells from the bone marrow to make way for the modified cells in Lenmeldy.
The safety and effectiveness of Lenmeldy was evaluated using data from 37 children who participated in two single-arm, open-label clinical trials and an expanded access program. Children who underwent treatment with Lenmeldy were compared to a group of untreated children, allowing for a comparison of their progress over time. The main measure of effectiveness was the duration of time without severe motor impairment, which was defined as the period from birth until the first instance of losing the ability to move and sit without assistance, or until death. In children diagnosed with MLD, the administration of Lenmeldy has shown significant effectiveness in reducing the likelihood of severe motor impairment or mortality when compared to children who did not receive treatment. At 6 years of age, all children who received treatment with Lenmeldy were still alive, in contrast to only 58% of children in the natural history group. By the age of 5, a significant majority of children who received treatment were able to walk without any help. The majority of the children who received treatment showed normal language and performance IQ scores, a finding that has not been observed in children who did not receive treatment. Furthermore, young patients who exhibited pre-symptomatic early juvenile and early symptomatic early juvenile MLD experienced a decline in motor and/or cognitive function.
Some potential side effects of Lenmeldy include fever, low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, gastrointestinal infections, and enlarged liver.
Following the administration of Lenmeldy, it is important to closely observe patients for any changes in neutrophil counts and the potential for delayed platelet engraftment until engraftment has been successfully accomplished. There are potential risks associated with Lenmeldy treatment, including the possibility of blood clot formation or the development of encephalitis, a swelling of the brain tissues. Although there is a potential risk of blood cancer, it is important to note that no cases have been observed in patients who have undergone treatment with Lenmeldy. It is important for patients to undergo regular monitoring for hematologic malignancies, which includes an annual complete blood count (with differential). Integration site analysis should also be considered, as needed, for a minimum of 15 years following treatment.
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At least two powerful earthquakes struck in southern Turkey and northern Syria in the early hours of Feb. 6. At least 6,200 people have been killed with thousands more injured. The real death toll and impact of the disaster, however, remains to be seen as emergency services race to rescue families and children trapped beneath the rubble.
The ICNA stands in support of the children, their families, our colleagues and others who have been affected by this natural disaster. We will never forget the warm Turkish hospitality we experienced during our recent ICNA congress 2022 in Antalya from the members of the Turkish Child Neurology Association. In solidarity, we offer our support to our many friends and colleagues and their families as well as to the vulnerable children they care for at this very sad and critical time of suffering and hope for the minimum of loss.
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Read more: Support the children and their families impacted by the Earthquake in Türkiye & Syria