Steve Pakola, MD, Chief Medical Officer for Regenxbio, discusses data from the ongoing gene therapy trials in children with mucopolysaccharidosis type I (MPS I) and mucopolysaccharidosis type II (MPS II). The data was presented at WORLDSymposium 2022.

MPS I is an inherited lysosomal storage disorder caused by a deficiency in the enzyme, alpha-L-iduronidase, which is responsible for breaking down glycosaminoglycans (GAGs). These GAGs accumulate in the tissues of MPS I patients, resulting in a diverse clinical profile. In moderate to severe forms of the disease, this accumulation in the central nervous system leads to hydrocephalus, spinal cord compression, and cognitive impairment. Additional symptoms may include clouded corneas; enlarged liver, spleen, and heart; noisy breathing; recurring upper respiratory tract; ear infections; difficulty swallowing; and periodic bowel problems.

MPS II is a rare, progressive lysosomal disease caused by deficient activity of iduronate-2-sulfatase, attributable to pathogenic variants of the iduronate-2-sulfatase gene (IDS). This disease has a variable clinical presentation but common signs and symptoms include: developmental decline between 18 and 36 months, followed by progressive loss of skills; coarse facial features; skeletal irregularities; obstructive airway and respiratory complications; joint stiffness; retinal degeneration; and communicating hydrocephalus.

Currently, the main treatment option for both MPS I and MPS II is enzyme replacement therapy (ERT). Unfortunately, intravenous iduronidase (for MPS I) and idursulfase (for MPS II) cannot pass the blood-brain barrier which makes it ineffective in treating neurological symptoms associated with severe forms of these lysosomal storage disorders.

As Dr. Pakola explains, RGX-111 and RGX-121 are both recombinant adeno-associated virus serotype 9 capsids containing the gene that encodes the alpha-L-iduronidase and iduronate-2-sulfatase enzyme, respectively. When administered to the central nervous system both investigational gene therapies may prevent the progression of cognitive deficits that otherwise occurs in MPS I and MPS II patients.