Intrathecal Gene Therapy Corrects CNS Pathology in a Feline Model of Mucopolysaccharidosis I

Abstract

Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases (LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing α-l-iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4-7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic.

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

“…The high vector copy numbers in the liver samples collected at necropsy rule out death of transduced hepatocytes as a cause of this decline as was seen previously when the normal canine IDUA cDNA was used in a retroviral vector (29). The kinetics of the loss of IDUA activity were identical to those observed in a previous study of CNS-directed gene therapy in feline MPS I, which were linked to the induction of antibodies against IDUA (30). Antibodies to IDUA were not detected by ELISA in the animal that exhibited a decline in expression in the present study (Fig.…”

“…High level expression was maintained for the duration of the study in three of the cats. The fourth animal (8958) exhibited a decline in The normal control animals (9110, 9115, 7704, 8991, 8992) and the untreated MPS I control animals (8922, 9052, 9055) were previously described (30). M, male; F, female.…”

“…Tissues were processed and stained as previously described (30). Trichrome staining was performed with a kit (Sigma Aldrich) according to the manufacturer's instructions.…”

A review of gene therapy in canine and feline models of lysosomal storage disorders

“…77 In addition, storage was reduced in livers of all treated animals, while those with low antibody titers exhibited cross-correction of the spleen. 77 Further studies with an intravenously delivered AAV8-fIDUA highlighted reversal of systemic storage lesions and complete correction of cardiovascular lesions in animals expressing sustained supraphysiological levels of IDUA in serum. 80 …”

Neuronopathic Types of Mucopolysaccharidoses: Pathogenesis and Emerging Treatments

“…Исследования интракраниальной генной терапии с применением аденоассоциированных, аденовирусных и лентивирусных векторов на экспериментальных живот-ных моделях МПС I, III и VII продемонстрировали возмож-ность распределения и экспрессии вирусных векторов, увеличение активности дефицитного фермента в голов-ном мозге, предотвращение и исчезновение отложений первичного субстрата, GM2-и GM3-ганглиозидов, умень-шение степени выраженности нейропатологических про-явлений, улучшение некоторых поведенческих и когни-тивных характеристик экспериментальных животных [41][42][43]. Опыт интратекального введения AAV9 кошачьим моделям МПС I также продемонстрировал коррекцию биохимических и гистологических характеристик ЦНС у экспериментальных животных [44].…”