The first tests on eight children show favorable preliminary results, with an adjustment of motor and cognitive skills and improvements in some brain and joint parameters

Gene therapy takes steps forward in the fight against rare diseases. Eight children with severe Hurler’s syndrome, a disease associated with reduced life expectancy, benefited from this therapy. The little ones are doing well, growing and have regained or maintained motor skills, skills that are severely compromised by the disease. The treatment, developed by the San Raffaele Telethon Institute for Gene Therapy in Milan (SR-Tiget), therefore shows a first favorable outcome. The results, still preliminary, are reported in an interim analysis (not yet the conclusive one, which contains the final data) published in the New England Journal of Medicine.

The severe Hurler syndrome

Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]) is the most severe phenotype of mucopolysaccharidosis type I, a rare autosomal recessive lysosomal storage disease caused by loss-of function variants of the IDUA gene, which encodes the enzyme α-L-iduronidase (IDUA); this loss of function leads to glycosaminoglycan (GAG) accumulation throughout peripheral organs and the central nervous system (CNS). Somatic clinical manifestations include coarse facial features, dysostosis multiplex, hepatosplenomegaly, hearing loss, visual impairment, upper airway obstruction, valvular heart disease, restrictive lung disease, brain atrophy, and spinal cord compression. Neurocognitive regression develops progressively in patients with MPSIH, and they die within their first decade of life.
Enzyme-replacement therapy (ERT) with Iaronidase reduces GAG accumulation and alleviates some somatic features.
However, skeletal and CNS manifestations are not controlled and anti-IDUA antibodies that develop in most patients may limit the efficacy of ERT.
Allogeneic hematopoietic stem-cell transplantation with pretransplantation or peritransplantation ERT is the standard of care for patients with MPSIH. Treated patients have high rates of overall survival, especially when treated at a
relatively young age and when cord-blood hematopoietic stem and progenitor cells (HSPCs) are used. Donor-derived hematopoietic cells constitute a stable endogenous source of the enzyme released into the systemic circulation and
locally in the tissues, from tissue-resident myeloid cells replaced after transplantation, which may cross-correct neighboring nonhematopoietic cells.
The latter mechanism may also support enzyme delivery into the CNS, lessening neurocognitive impairment with hematopoietic stem-cell transplantation as compared with ERT.

However, cognitive and skeletal abnormalities persist and progress over time after allogeneic hematopoietic stem-cell transplantation, severely affecting patients’ quality of life.

A new strategy was designed by Authors based on genetic engineering of autologous HSPCs to drive supranormal IDUA activity that is distributed to affected tissues through the turnover of resident hematopoietic cells. In a mouse model of mucopolysaccharidosis type I, was found that disease manifestations, including the neurologic and skeletal defects, were corrected with lentiviral vector–based HSPC gene therapy with superior proficiency as compared with hematopoietic stem-cell transplantation from wild-type donors, probably owing to higher IDUA expression from the engineered cassette with respect to the endogenous locus.

In this paper are reported the interim safety and efficacy results of eight patients with MPSIH treated with autologous HSPCs genetically modified to overexpress human IDUA, with follow-up ranging from 1.46 to 2.90 years.

In all of the young patients, the new cells with gene correction resulted effective within one month of transplantation and the result is being maintained in subsequent monitoring. The activity of the enzyme has been detected and is associated with the local elimination of large molecules called mucopolysaccharides, the accumulation of which is the basis of various symptoms of the disease. The brain and movement also benefited. In the preliminary analysis, in fact, the patients showed a stable cognitive performance, while the motor development proceeded and the ability to move did not decrease. The images of the brain and spine obtained with MRI also show consistent results and in some cases even improvements, along with a reduction in joint stiffness. The growth, then, is in line with the normal one according to the parameters indicated by the World Health Organization.

These first results, still initial, but promising, seem to indicate – and the hope is that in the future there will be confirmation, with lasting results – that the correction of the gene defect has been acquired and is effective.