Gene therapy of hematological disorders: current challenges.

Recent advances in genetic engineering technology and stem cell biology have spurred great interest in developing gene therapies for hereditary, as well as acquired hematological disorders. Currently, hematopoietic stem cell transplantation is used to cure disorders such as hemoglobinopathies and primary immunodeficiencies; however, this method is limited by the availability of immune-matched donors. Using autologous cells coupled with genome editing bypasses this limitation and therefore became the focus of many research groups aiming to develop efficient and safe genomic modification. Hence, gene therapy research has witnessed a noticeable growth in recent years with numerous successful achievements; however, several challenges have to be overcome before gene therapy becomes widely available for patients. In this review, I discuss tools used in gene therapy for hematological disorders, choices of target cells, and delivery vehicles with emphasis on current hurdles and attempts to solve them, and present examples of successful clinical trials to give a glimpse of current progress.

Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.

INTRODUCTION: ADCY5-related hyperkinesia encompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesia were associated with an autosomal dominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomal recessive ADCY5-related disorder and expand the genotypic and phenotypic spectrum of this disorder. METHODS: The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing (WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family. RESULTS: All patients presented with early-onset dystonia and myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomal recessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious. CONCLUSION: This study reports the second family with autosomal recessive childhood-onset ADCY5-related disorder and expands our understanding of phenotype/genotype correlations of this disorder.

Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson's disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared. Here we show that proteins from different species have different biochemical properties, with the mouse protein being more stable but having significantly lower kinase activity compared to the human orthologue. In examining the effects of PD-associated mutations and risk factors on protein function, we found that conserved substitutions such as G2019S affect human and mouse LRRK2 proteins similarly, but variation around position 2385, which is not fully conserved between humans and mice, induces divergent in vitro behavior. Overall our results indicate that structural differences between human and mouse LRRK2 are likely responsible for the different properties we have observed for these two species of LRRK2 protein. These results have implications for disease modelling of LRRK2 mutations in mice and on the testing of pharmacological therapies in animals.