Thursday, August 13, 2020

Transplantation and gene therapy in inborn errors

Tan EY, Boelens JJ, Jones SA, Wynn RF. Hematopoietic Stem Cell Transplantation in Inborn Errors of Metabolism. Front Pediatr. 2019;7:433. Published 2019 Oct 25. doi:10.3389/fped.2019.00433


Hematopoietic stem cell transplantation (HSCT) has been established as an effective therapy for selected inborn errors of metabolism. The success of HSCT in metabolic disease is best exemplified through the treatment of Hurler's syndrome, a lysosomal storage disease. Through the collaborative effort of several international centers, factors that predict successful patient and transplant outcomes have been identified. In this review, we discuss the principles that underlie the use of HSCT in metabolic diseases. We consider the clinical indications, conditioning regimens, and disease-specific follow-up for HSCT in different metabolic diseases. We highlight persisting challenges in HSCT to delay progression of certain organ systems that remain refractory to HSCT and the relatively high rates of aplastic graft failure. Finally, we evaluate the variable applicability of these principles to other inherited metabolic disorders including peroxisomal, mitochondrial, and other lysosomal storage diseases.


 From the article: 

There is no role for HSCT in Sanfilippo syndrome (MPS III) or infantile Metachromatic Leukodystrophy (MLD). MLD is caused by deficiency of arylsulfatase A and subsequent accumulation of sulfatides in the central and peripheral nervous system, resulting in widespread demyelination. What has been learnt from MPS IH has not reliably translated to infantile MLD or MPS III. Despite pre-symptomatic HSCT and utilization of UCB, HSCT does not halt disease progression in infantile MLD (brain seems modified, but peripheral nerve system not) or MPS III. Patient outcomes for infantile MLD following HSCT is complicated by peripheral neuropathy and significant HSCT-associated morbidity. Even with full engraftment in MPS III patients, there is no biochemical correction of the disease in the CSF. In MLD, transplant failure may be largely attributable to the slow and gradual replacement of resident tissue macrophages and microglia populations by donor-derived progeny compared with the rapid progression of disease. Furthermore, donor-derived microglial cells may secrete insufficient amounts of enzyme to correct neuronal tissue in these LSDs. Ex-vivo stem cell gene therapy of autologous HSC improves graft enzyme delivery and has been shown to be dramatically beneficial in modifying disease progression in infantile MLD (see the review “Autologous stem cell-based gene therapy for inherited disorders: state-of-the-art and future prospects”).

Staal FJT, Aiuti A, Cavazzana M. Autologous Stem-Cell-Based Gene Therapy for Inherited Disorders: State of the Art and Perspectives. Front Pediatr. 2019;7:443. Published 2019 Oct 31. doi:10.3389/fped.2019.00443


Gene therapy using patient's own stem cells is rapidly becoming an alternative to allogeneic stem cell transplantation, especially when suitably compatible donors cannot be found. The advent of efficient virus-based methods for delivering therapeutic genes has enabled the development of genetic medicines for inherited disorders of the immune system, hemoglobinopathies, and a number of devastating metabolic diseases. Here, we briefly review the state of the art in the field, including gene editing approaches. A growing number of pediatric diseases can be successfully cured by hematopoietic stem-cell-based gene therapy. ___________________________________________________________________________

From the article:

Allo-HSCT is sometimes used to treat various metabolic diseases, and especially lysosomal storage diseases. The latter are caused by mutations in one of ~50 enzymes that break down large molecules (glycoproteins, lipids, glycogen, etc.) and pass the fragments on to other parts of the cell for recycling. Allo-HSCT has been used successfully to treat lysosomal storage diseases, and particularly mucopolysaccharidosis. The idea is that monocytes/macrophages can penetrate into many organs and thus supply the missing enzyme to various tissues, including bone, muscle, and brain. In this context, gene therapy with autologous cells has an additional advantage: depending on the vector's promoter, the therapeutic genes can be expressed at much higher levels than those normally present in HSCs and their offspring—thereby providing greater clinical benefit than allo-HSCT. This approach has produced spectacular results in patients with metachromatic leukodystrophy, with high-level production of the arylsulfatase enzyme in HSCs, mature blood cells, and central nervous system cells. This production prevented disease onset or halted disease progression, relative to untreated patients enrolled in a natural history study—especially when treatment was given before the onset of any clinical symptoms. In a clinical trial in X-linked adrenoleukodystrophy, the majority of patients had stable neurological function more than 2 years after gene therapy. 

Ohashi T. Gene therapy for lysosomal storage diseases and peroxisomal diseases. J Hum Genet. 2019;64(2):139-143. doi:10.1038/s10038-018-0537-5


Gene therapies for lysosomal storage diseases (LSD) and peroxisomal diseases (PD) are rapidly advancing. Most LSDs and PDs are characterized by brain involvement, prompting the development of therapies targeting the brain. There are two types of gene therapy for brain involvement in LSD and PD, i.e., the direct transfer of a therapeutic gene into brain cells and hematopoietic stem cell-targeted gene therapy. The rationale for the latter approach is that brain microglia are derived from hematopoietic cells. Thus, gene-corrected hematopoietic cells migrate into the brain and differentiate into microglial cells. These gene-corrected microglial cells correct the metabolic defects associated with LSD and reduce inflammation in PD and LSD, leading to a clinical benefit. Gene editing technology has recently been applied in this area and a trial focused on LSD is currently ongoing. Although these approaches are still under investigation, very encouraging results have been obtained. This review provides an overview of recently developed gene therapies for various LSDs and PDs, including the results of clinical trials, with an emphasis on the benefits of this approach for these diseases.

Martinez-Morga M, Medina-Corvalan C, Pérez-García C, Bueno C, Martinez S. Mecanismo de acción de la terapia celular en enfermedades hereditarias [Mechanism of action of cell therapy in hereditary diseases]. Medicina (B Aires). 2020;80 Suppl 2:2-6.


Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

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