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IDS crossing of the blood-brain barrier corrects CNS defects in MPSII mice
Vinicia Assunta Polito1, Maria Pia Cosma
1Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Abstract:
Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, arises from a deficiency in iduronate 2-sulfatase (IDS), and it is characterized by progressive somatic and neurological involvement. The MPSII mouse model reproduces the features of MPSII patients. Systemic administration of the AAV2/5CMV-hIDS vector in MPSII mouse pups results in the full correction of glycosaminoglycan (GAG) accumulation in visceral organs and in the rescue of the defects and GAG accumulation in the central nervous system (CNS). Remarkably, in treated MPSII animals, this CNS correction arises from the crossing of the blood-brain barrier by the IDS enzyme itself, not from the brain transduction. Thus, we show here that early treatment of MPSII mice with one systemic injection of AAV2/5CMV-hIDS results in prolonged and high levels of circulating IDS that can efficiently and simultaneously rescue both visceral and CNS defects for up to 18 months after therapy.
Insights
Early systemic gene therapy for Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, in mice led to sustained enzyme levels. This corrected both visceral organ and central nervous system (CNS) damage for 18 months.
Area of Science:
- Gene therapy
- Biochemistry
- Neurology
Background:
- Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, is a genetic disorder caused by iduronate 2-sulfatase (IDS) deficiency.
- MPSII leads to progressive somatic and neurological damage, with a mouse model accurately reflecting human patient features.
Purpose of the Study:
- To evaluate the efficacy of systemic AAV2/5CMV-hIDS vector administration in correcting MPSII manifestations in a mouse model.
- To determine if systemic treatment can rescue central nervous system (CNS) defects by enzyme crossing of the blood-brain barrier.
Main Methods:
- Systemic administration of the AAV2/5CMV-hIDS vector in MPSII mouse pups.
- Monitoring of glycosaminoglycan (GAG) accumulation in visceral organs and the CNS.
- Assessment of IDS enzyme levels in circulation and its ability to cross the blood-brain barrier.
Main Results:
- Systemic vector injection fully corrected GAG accumulation in visceral organs.
- Treated MPSII mice showed rescue of CNS defects and GAG accumulation.
- CNS correction was attributed to circulating IDS enzyme crossing the blood-brain barrier, not direct brain transduction.
Conclusions:
- Early, single systemic injection of AAV2/5CMV-hIDS in MPSII mice results in prolonged, high circulating IDS levels.
- This treatment efficiently and simultaneously rescues both visceral and CNS defects for up to 18 months.
- Systemic gene therapy offers a promising therapeutic strategy for MPSII, addressing both peripheral and neurological manifestations.
