抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia The β-haemoglobinopathies are the most prevalent inherited disorders worldwide Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2 The βE-globin allele bears a point mutation that causes alternative splicing The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2 When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2 The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells

Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

Mononuclear phagocytic cells in the CNS used to be defined according to their anatomical location and surface marker expression. Recently, this concept has been challenged by the results of developmental and gene expression profiling studies that have used novel molecular biological tools to unravel the origin of microglia and to define their role as specialized tissue macrophages with long lifespans. Here, we describe how these results have redefined microglia and helped us to understand how different myeloid cell populations operate in the CNS based on their cell-specific gene expression signatures, distinct ontogeny and differential functions. Moreover, we describe the vulnerability of microglia to dysfunction and propose that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.

Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.

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Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.

Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

Gene therapy returns to centre stage

X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate–binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34 + cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 , and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.

https://science.sciencemag.org/content/sci/326/5954/818.full.pdf

Bruno l’Homme

Papers

Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy