The gene-edited approach hopes to overcome with the shortcomings of autologous hematopoietic stem-cell transplantation.
Autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an IDUA–encoding lentiviral vector yielded extensive metabolic correction in peripheral tissues and the central nervous system in patients with Hurler syndrome (mucopolysaccharidosis type 1, Hurler variant (MPSIH), according to data from a recent phase 1/2 study (NCT03488394) reported in the New England Journal of Medicine.1
The therapy was relatively well-tolerated, with a safety profile similar to autologous hematopoietic stem-cell transplantation (AHSCT) over a median follow-up of 2.10 years. Gene-corrected cells were promptly engrafted and this engraftment was sustained. Patients had supraphysiologic blood IDUA activity within a month maintained to the latest follow-up, and previously undetectable IDUA levels in cerebrospinal fluid (CSF) became detectable after gene therapy.
“Until now, definitive treatment has been allogeneic hematopoietic-cell transplantation (HCT)... however, allogeneic HCT is fraught with numerous potential issues, including the need to find a donor who is reasonably HLA-matched to the patient; the need for... myeloablation; and the need for ongoing immunosuppression to prevent... graft-versus-host disease (GVHD),” Sandhya Kharbanda, MD, and Christopher C. Dvorak, MD, wrote in a related editorial.2
“Well-matched umbilical-cord blood units have been considered the preferred HSC source owing to increased rates of full donor chimerism and higher enzyme levels than with other stem-cell sources. However, umbilical-cord blood HCTs are fraught with delayed or absent engraftment, slow immunologic reconstitution, and a high incidence of post-HCT autoimmunity, especially among patients with Hurler syndrome,” Kharbanda and Dvorak continued.2
The study, conducted by first author Bernard Gentner, MD, and colleagues, has enrolled 8 children with MPSIH without moderate or severe cognitive impairment (Developmental Quotient [DQ] or Intelligence Quotient [IQ] score > 70) that lacked a suitable allogeneic donor. The children had a mean age of 1.9 years (standard deviation, 0.5).
The participants received the edited HSPCs after myeloablative conditioning. The study’s primary outcome measures are safety and correction of blood IDUA activity to supraphysiologic levels. Secondary and exploratory end points include clearance of lysosomal storage material and skeletal and neurophysiological development. The study’s planned duration is 5 years.
Peripheral-blood mononuclear cells (PBMCs) reached a median vector copy number of 0.98 per genome (range, 0.17-3.95) at 9 to 12 months after HSPC gene therapy. Five patients (62%) had long-term engraftment levels above 30% of transduced PBMCs. Multiple hematopoietic lineages from both peripheral blood and bone marrow had similar gene marking.
Investigators found that urinary glycosaminoglycan (GAG) excretion decreased steeply to normal levels at 12 months in 4 of 5 evaluable patients. Associated with GAG clearance was newly detectable IDUA CSF activity. Blood IDUA activity reached supraphysiologic levels as early as 30 days after treatment in all patients. This activity persisted through 12 months in all patients (median, 108.0 μmol/L/hr; range, 30.0-138.6) and was above the 97.5th percentile in age-matched, healthy children.
All participants progressively acquired motor skills over time via stable Total, Gross, and Fine Motor Quotient scores. Six participants had normal performance and 2 were below the normal range at last follow-up. Investigators also observed progressive gain of cognitive and language skills regardless of baseline DQ or IQ score.
White matter and perivascular-space abnormalities were reduced from baseline on magnetic resonance imaging (MRI) 12- and 24-months post-therapy in 3 of 5 and 2 of 3 evaluable patients, respectively. The remaining participants’ alterations were stable. All participants continued to have normal growth throughout follow-up in line with World Health Organization growth charts.
The therapy had a similar safety profile to AHSCT. Grade 4 thrombocytopenia occurred in 3 patients, each on a single day; these patients had an early, spontaneous platelet recovery (median, day 14; range, 12-19). Lymphocyte counts recovered 1 month after treatment. In total, 19 serious adverse events (AEs) occurred and 7 (37%) were related to the indication and present before therapy. One AE, an acute hypersensitivity reaction was considered probably related to HSPC gene therapy although this resolved after treatment with antihistamines, intravenous fluids, and glucocorticoids, with no sequelae.
“Despite... unanswered questions, Gentner et al. are to be congratulated for moving the field one step closer to an idealized therapy that will someday result in complete correction of Hurler syndrome with minimal toxic effects and, hopefully, reasonable costs and broad access regardless of socioeconomic status,” Kharbanda and Dvorak wrote.2