Novel lentiviral vector advances gene therapy for rare neurological disease
An approved gene therapy has been modified with a new lentiviral vector, demonstrating improved safety and expanding the eligibility criteria.
A preclinical study conducted by researchers at Children’s Hospital of Philadelphia (PA, USA) has demonstrated an improved gene therapy approach for metachromatic leukodystrophy (MLD), a rare, progressive pediatric neurological disease. The team generated a novel lentiviral vector capable of enhancing the therapy’s efficiency and expanding eligibility for patients, offering new hope for treating the disease.
MLD affects approximately one in 40,000 individuals, primarily children, and results from the deficiency of arylsulfatase A (ARSA), an enzyme essential for breaking down sulfatides. A build-up of sulfatides can become toxic over time, injuring the myelin, leading to a decrease in neurological skills and potentially, early death.
Currently, the gene therapy atidarsagene autotemcel, is approved in the US and Europe for MLD, providing a treatment option for pre-symptomatic and early-symptomatic patients. This therapy involves ex vivo modification of a patient’s hematopoietic stem cells by introducing a functional ARSA gene. The modified cells are then transplanted back into the patient to engraft in the bone marrow, where they begin to grow and enable the immune cells to produce the ARSA enzyme. However, this treatment is only effective for early-stage patients, leaving those with later-onset forms, such as late juvenile MLD, ineligible for the therapy.
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To broaden the therapy’s use for more MLD patients, the researchers designed a novel lentiviral vector, EA1. This top-performing vector uses elongation factor 1 alpha (EF1α) to drive transcription of the ARSA gene. Additionally, the researchers engineered their lentivirus to include insulator elements, which help prevent the unwanted activation of nearby genes and reduce incorrect transcription caused by viral integration. They also incorporated a low vector copy number (VCN) to minimize the risk of genotoxicity and lower production costs, enhancing both the safety and accessibility of the therapy.
The researchers compared the effects of the original gene therapy with their version using the new lentiviral vector (EA1), testing ARSA expression and enzymatic activity in stem cells derived from both a healthy individual and a patient with MLD. As expected, ARSA activity increased in cells treated with the original gene therapy. However, the EA1-treated cells had a four-fold greater ARSA activity in ARSA-deficient fibroblasts compared to the cells treated with the original gene therapy.
Next, the team applied their approach to a mouse model of MLD. They found that mice receiving EA1 performed significantly better, achieving therapeutic effects with five times lower VCN than previous approaches. The new vector also demonstrated an enhanced ability to secrete vesicle-associated ARSA, a crucial mechanism for enzyme transfer within the brain.
The study’s findings suggest that EA1 has the potential to increase the safety and efficiency of gene therapy for MLD, with broader applicability to related leukodystrophies, such as multiple sulfatase deficiency.
“We’ve shown that achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low VCN is essential in order to maximize the clinical benefit while minimizing risks and costs,” said first author Lucas Tricoli.
The research team is now preparing an Investigational New Drug application with the Food and Drug Administration (MD, USA) to assess the safety and efficacy of the modified therapy. If successful, this improved gene therapy could expand treatment eligibility and provide a more effective, accessible option for MLD patients.
