Haematopoietic stem cell gene therapy in inborn errors of metabolism

Abstract

Inborn errors of metabolism (IEM) constitute a heterogeneous group of single gene diseases, which cause the deficiency of critical enzymes involved in cell metabolism. The enzymatic insufficiency leads to the disruption of critical biological pathways, with accumulation of toxic metabolites in different human cells and tissues. This can lead to complex, life-threatening syndromes, affecting the skeletal structure, vision, hearing, cardiopulmonary function and neurological development. The reported cumulative incidence of IEM differs across the world, with an estimated incidence of 1:667 in Saudi Arabia and 1:2920 in Germany. 1 Current therapeutic strategies for IEM are directed towards reducing critical substrates, removing toxic metabolites or increasing the activity of the defective enzyme.Enzyme-replacement therapy (ERT) relies on the recombinant production of highly purified enzymes administered to patients affected by a number of IEM, in order to crosscorrect tissues and organs suffering from that enzymatic

Current and Future Perspective in Hematopoietic Stem Progenitor Cell-gene Therapy for Inborn Errors of Metabolism

“…39 Overall, HSPC-GT holds a favorable safety profile requiring short hospitalization due to prompt engraftment, with very limited transplant-related complications. 24 This, in turn, could positively impact on neurological and skeletal functions of patients affected by IEM. 40 Another significant advantage of using autologous cells is that there is no need of searching for a suitable donor, while HSCT frequently depends on the availability of unrelated compatible donors, as potentially HLA-matched siblings or family members are often disease carriers, not candidates as donors.…”

“…Another significant advantage of using autologous cells is that there is no need of searching for a suitable donor, while HSCT frequently depends on the availability of unrelated compatible donors, as potentially HLA‐matched siblings or family members are often disease carriers, not candidates as donors. Thus, employing autologous HSPC allows timely transplantation, which is crucial for long‐term clinical outcome in IEM 24 . Precocious recognition of these disorders by newborn screening (NBS) could enable early diagnosis 41 and treatment at presymptomatic, currently possible only for patients with a positive family history, further optimizing clinical results with HSPC‐GT strategies.…”

“…Following these results, HSPC‐GT for CALD has been approved both in US 23 and Europe with the aim to slow the progression of neurologic dysfunction in boys 4–17 years of age with early active CALD; however, it was withdrawn from the EU market for commercial reasons. While HSPC‐GT and HSCT seem equally effective in preventing disease progression in patients with early‐stage CALD and HSPC‐GT is known to be associated with reduced transplant‐related complications, 3 cases of myelodysplasia (MDS) have been recently reported after HSPC‐GT 22 , 24 …”

“…According to the current evidence, the development of MDS was mediated by Lenti‐D LV insertion. Specific design features of this vector, such as the presence of the MNDU3 promoter enabling ubiquitous expression of the ABCD1 transgene in blood lineage, likely contributed to the development of MDS 24 . However, after having placed a clinical hold on this product, on September 2022, FDA approved it with a boxed warning for hematologic malignancy, including life‐threatening cases of MDS, based on the cost‐benefit analysis 23…”

“…While HSPC-GT and HSCT seem equally effective in preventing disease progression in patients with early-stage CALD and HSPC-GT is known to be associated with reduced transplant-related complications, 3 cases of myelodysplasia (MDS) have been recently reported after HSPC-GT. 22,24 MPS are a group of LSD caused by deficiency in glycosaminoglycans (GAG) breakdown. The clinical manifestations include somatic and neurological symptoms, depending on the type of accumulated GAG.…”