Positive Data from Two Gene Therapy Trials for MPS I and MPS II

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.
In the phase 1/2, multicenter, open-label, dose escalation trial for RGX-111, participants with CNS involvement or severe MPS I 4 months of age or older receive one image-guided RGX-111 injection to the CNS with 104 week follow-up for safety, tolerability, and efficacy. Assessments include cerebrospinal fluid, plasma, and urine biomarkers; cognitive, language, and motor neurodevelopmental scales; and imaging. Two subjects have been dosed at Dose 1 (1.0 x 1010 genome copies/g brain mass) and three subjects have currently been dosed at Dose 2 (5.0 x 1010 genome copies/g brain mass). Enrollment for Dose 2 continues. Overall, all participants have shown continued skill acquisition within two standard deviations of the norm with regard to cognition, expressive language and fine motor subtests at last assessment.

In the phase 1/2, multicenter, open-label, dose escalation trial for RGX-121, RGX-121 is administered directly to the CNS. Patients are treated across three dose levels: 1.3x1010 genome copies per gram (GC/g) of brain mass (n=3), 6.5x1010 GC/g of brain mass (n=7), and 2.9x1011 GC/g of brain mass (n=3). As of December 20, 2021, RGX-121 is reported to be well-tolerated across all cohorts with no drug-related serious adverse events. Eight patients were receiving weekly enzyme replacement therapy (ERT) at the time of enrollment and of those, three have discontinued ERT. The majority of patients in all three cohorts demonstrated reductions of heparan sulfate and D2S6 in the CSF following RGX-121 administration. Finally, urine GAG measures showed evidence of systemic effect of RGX-121 independent of ERT treatment.

To learn more about MPS I, MPS II, and other rare lysosomal storage disorders, visit https://checkrare.com/diseases/lysoso...