Abstract
Mucopolysaccharidosis type I is a recessive genetic disease caused by deficiency of the lysosomal enzyme α-L-iduronidase, which leads to a neurodegenerative and systemic disease called Hurler syndrome in its most severe form. Several clinical trials are evaluating adeno-associated virus serotype 9 (AAV9) for the treatment of neurodegenerative diseases. Although these trials focus on systemic or lumbar administration, intrathecal administration via suboccipital puncture into the cisterna magna has demonstrated remarkable efficacy in large animals. We, therefore, conducted a good laboratory practice-compliant non-clinical study to investigate the safety of suboccipital AAV9 gene transfer of human α-L-iduronidase into nonhuman primates. We dosed 22 rhesus macaques, including three immunosuppressed animals, with vehicle or one of two doses of vector. We assessed in-life safety and immune responses. Animals were euthanized 14, 90, or 180 days post-vector administration and evaluated for histopathology and biodistribution. No procedure-related lesions or adverse events occurred. All vector-treated animals showed a dose-dependent mononuclear pleocytosis in the cerebrospinal fluid and minimal to moderate asymptomatic degeneration of dorsal root ganglia neurons and associated axons. These studies support the clinical development of suboccipital AAV delivery for Hurler syndrome and highlight a potential sensory neuron toxicity that warrants careful monitoring in first-in-human studies.
Highlights
Mucopolysaccharidosis type I (MPS I) is a rare inherited disorder caused by mutations in the gene encoding a-L-iduronidase (IDUA), a lysosomal enzyme required for degradation of glycosaminoglycans, including heparan sulfate and dermatan sulfate
With the goal of safely and rapidly reconstituting therapeutic levels of IDUA activity in the CNS, we developed an approach in which the IDUA coding sequence expressed from a strong ubiquitous promoter is delivered to cells throughout the CNS using an adeno-associated virus (AAV) vector injected into the cerebrospinal fluid (CSF)
We evaluated a high dose (HD) of 1 Â 1013 genome copies (GCs; n = 15) at three different time points (14, 90, and 180 days postinjection) and a low dose (LD) of 1 Â 1012 GCs (n = 3; 90 days postinjection) compared with vehicle control (n = 4)
Summary
Mucopolysaccharidosis type I (MPS I) is a rare inherited disorder caused by mutations in the gene encoding a-L-iduronidase (IDUA), a lysosomal enzyme required for degradation of glycosaminoglycans, including heparan sulfate and dermatan sulfate. Preclinical studies in naturally occurring canine and feline models of MPS I demonstrated that a single minimally invasive injection of an AAV serotype 9 (AAV9) vector into the cisterna magna (ICM) can achieve high levels of IDUA activity in the CSF within a week of administration, leading to the resolution of storage lesions throughout the brain.[12,13,14] The ICM approach results in superior CNS distribution of AAV vectors compared with other routes of CSF access but is not commonly utilized in clinical practice,[15]. The size and anatomic similarity of nonhuman primates to humans make them a relevant model to evaluate vector biodistribution after ICM injection and any toxicity associated with vector delivery to target cells
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