Gene Therapy (RGX-111) to Treat Mucopolysaccharidosis Type I (MPS I)

Описание: Raymond Wang, MD, Metabolic Specialist and Director of the Multidisciplinary Lysosomal Storage Disorder Program at Children's Hospital of Orange County, discusses RGX-111, an investigational gene therapy for mucopolysaccharidosis type I (MPS I). Data from this study was recently 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). In moderate to severe forms of the disease, the accumulation of GAGs 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.

Currently, there are two main treatment options for MPS I – enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). ERT involves intravenous iduronidase which is a life-long treatment usually given every week. Unfortunately, intravenous iduronidase cannot pass the blood-brain barrier which makes it ineffective in treating neurological symptoms associated with severe MPS I. HSCT is effective in treating neurological symptoms; however, this therapy requires the patient to undergo chemotherapy to eliminate their own stem cells before receiving the foreign, healthy stem cells. In addition, graft-versus-host disease is a concern with HSCT. As both of these treatment options have significant disadvantages, there has been a push for companies to develop a gene therapy for MPS I, which, if successful, would be curative.

As Dr. Wang explains, RGX-111 is a recombinant adeno-associated virus serotype 9 capsid containing a human IDUA expression cassette (AAV9.CB7.hIDUA). When administered to the central nervous system (CNS), RGX-111 may provide a permanent CNS source of secreted alpha-L-iduronidase, potentially preventing the progression of cognitive deficits that otherwise occurs in MPS I patients. In this phase 1/2, first-in-human, multicenter, open-label, dose escalation trial, participants CNS involvement or severe MPS I, four months of age or older, received 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 3 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 showed continued skill acquisition within 2 standard deviations of normative mean on the cognition, expressive language and fine motor subtests at last assessment and cognitive function has remained within 2 standard deviations of normative range at the last assessment, 20 months after RGX-111 administration.
Dr. Wang also discusses the 2-year follow-up for a severe MPS I child treated at age 21 months utilizing a single-patient, investigator-initiated Investigational New Drug application. As Dr. Wang says, this patient is one of four brothers with severe MPS I. Unfortunately, two of his brothers died from complications with HSCT. The patient given gene therapy is presenting with significantly less severe symptoms following treatment with RGX-111 compared to his oldest brother’s symptoms at the same age.