Four of 5 patients showed improvements in ejection fraction following bone marrow transplant.
Hematopoietic Cell Transplantation (HCT) appeared to resolve ventricular hypertrophy and to improve systolic ventricular function in a retrospective chart review of patients with the Hurler subtype of mucopolysaccharidosis type I (MPS-IH).1 The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.
While enzyme replacement therapy (ERT) and HCT are established standards of care for MPS IH, there is a lack of data on the effects of HCT on decreased cardiac function for patients with MPS-IH. Nishitha R. Pillai, Division of Genetics and Metabolism, Department of Pediatrics, University of Minnestoa, and colleagues evaluated records of 5 patients with MPS-IH who had been treated with HCT at the University of Minnesota between June 2012 and June 2022.
The patients included Patient 1 (P1), a female patient who was diagnosed with MPS-IH at 21 months (m) and began ERT at 21 m; P2, a female patient diagnosed at 1 week (w) who began ERT at 6 w; P3, a female patient diagnosed at 9 m who began ERT at 11 m; P4, a male patient diagnosed at 1 w who began ERT at 4 w; and P5, a male patient diagnosed at 4 m who began ERT at 18 m. P1 and P5 had a diminished left ventricular ejection fraction (LVEF) at diagnosis while P2-4 had a diminished LVEF and mild mitral valve insufficiency (MVI) at diagnosis. Pillai and colleagues noted that EF at the time of diagnosis or initial cardiac evaluation ranged from 22% to 47% (mean, 32%), all of which are lower than normal (55%). Following treatment with ERT for 1 to 6 months (mean, 4), 3 of the 5 patients continued to have low EFs ranging from 26% to 45% (mean, 36%) and began treatment with milrinone. Milrinone improved the EF in these individuals, though their EFs still remained below normal.
P1 received bone marrow transplant (BMT) at 29 m, P2 received BMT at 4 m, P3 received BMT at 14 m, P4 received BMT at 5 m, and P5 received BMT at 10 m. All of the patients, except P2, showed an additional increase in EF, putting them into the normal range, following BMT. While P2 had an EF of 70% at the time of BMT, her most recent EF was 54%.
P1’s current age is 12 years (y), and her most recent echocardiogram findings included trivial tricuspid regurgitation (TR), aortic regurgitation (AR) and pulmonic regurgitation (PR), and mild thickening of mitral and aortic valve leaflets. P2’s current age is 4 y and her most recent echocardiogram findings included mild MVI and dilation of proximal ascending aorta (Z score, 2.4). P3’s current age is 3 y and her most recent echocardiogram findings included mild MVI, mild thickening of aortic and mitral valves, and dilation of aortic valve annulus (Z score, 2.3). P4’s current age is 2 y and his most recent echocardiogram findings included mild MVI, mild thickening of aortic and mitral valve, and dilation of aortic valve annulus (Z score, 2.3). P5 died of drug-resistant sepsis while still on milrinone. He had a normal (53%) EF at the time of death. It was noted that P1 and P4 successfully discontinued milrinone after complete engraftment.
Pillai and colleagues concluded that “long-term ERT as well as HCT appear to resolve ventricular hypertrophy and improve the systolic ventricular function.” They noted that the fact that P4 showed thickening of the mitral aortic valves even though he was diagnosed and treated early calls into question the benefit of early treatment on cardiac outcomes. Furthermore, P2, P3, and P4 developed aortic root and ascending aortic dilation after HCT even though they had received early diagnosis and treatment.
Several gene therapies are currently in development for MPS subtypes, including MPSI. Data from a phase 1/2 trial (NCT03580083) of RGX-111, REGENXBIO’s investigational gene therapy for the treatment of MPSI, was also presented at WORLDSymposium.2 RGX-111 was well-tolerated and showed signs of efficacy in children in the trial as well as in 1 child treated under a single-patient investigational new drug (IND) application. Meanwhile, Orchard Therapeutics’ OTL-203, an investigational hematopoietic stem cell gene therapy intended to treat MPS-IH, received clearance of its IND application from the FDA in January 2023.3
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