Progress and challenges in viral vector manufacturing
Promising results in several clinical studies have emphasized the potential of gene therapy to address important medical needs and initiated a surge of investments in drug development and commercialization. This enthusiasm is driven by positive data in clinical trials including gene replacement for Hemophilia B, X-linked Severe Combined Immunodeficiency, Leber's Congenital Amaurosis Type 2 and in cancer immunotherapy trials for hematological malignancies using chimeric antigen receptor T cells. These results build on the recent licensure of the European gene therapy product Glybera for the treatment of lipoprotein lipase d...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: van der Loo, J. C. M., Wright, J. F. Tags: INVITED REVIEWS Source Type: research
Adeno-associated viral vectors for the treatment of hemophilia
Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucid...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: High, K. A., Anguela, X. M. Tags: INVITED REVIEWS Source Type: research
Progress toward improved therapies for inborn errors of metabolism
Because of their prevalence, severity and lack of effective treatments, inborn errors of metabolism need novel and more effective therapeutic approaches. The opportunity for an early treatment coming from expanded newborn screening has made this need even more urgent. To meet this demand, a growing number of novel treatments are entering in the phase of clinical development. Strategies to overcome the detrimental consequences of the enzyme deficiencies responsible for inborn errors of metabolism have been focused on multiple fronts at the levels of the gene, RNA, protein and whole cell. These strategies have been accomplis...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Ginocchio, V. M., Brunetti-Pierri, N. Tags: INVITED REVIEWS Source Type: research
Gene-targeting pharmaceuticals for single-gene disorders
The concept of orphan drugs for treatment of orphan genetic diseases is perceived enthusiastically at present, and this is leading to research investment on the part of governments, disease-specific foundations and industry. This review attempts to survey the potential to use traditional pharmaceuticals as opposed to biopharmaceuticals to treat single-gene disorders. The available strategies include the use of antisense oligonucleotides (ASOs) to alter splicing or knock-down expression of a transcript, siRNAs to knock-down gene expression and drugs for nonsense mutation read-through. There is an approved drug for biallelic...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Beaudet, A. L., Meng, L. Tags: INVITED REVIEWS Source Type: research
Progress and prospects of gene therapy clinical trials for the muscular dystrophies
Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin–glycoprotein compl...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Bengtsson, N. E., Seto, J. T., Hall, J. K., Chamberlain, J. S., Odom, G. L. Tags: INVITED REVIEWS Source Type: research
Advances in treatment of achondroplasia and osteoarthritis
Achondroplasia (ACH) is the prototype and most common of the human chondrodysplasias. It results from gain-of-function mutations that exaggerate the signal output of the fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. Five show promise in preclinical mouse studies. Two candidate therapies target the extracellular domain of FGFR3. The first is a decoy receptor that competes for activating ligands. The ...
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Klag, K. A., Horton, W. A. Tags: INVITED REVIEWS Source Type: research
Gene therapy grows up (and moves out of the house)
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 21, 2016 Category: Genetics & Stem Cells Authors: Davidson, B. L., Lee, B. Tags: EDITORIALS Source Type: research
Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at tw...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Johansson, A., Eriksson, N., Lindholm, D., Varenhorst, C., James, S., Syvänen, A.-C., Axelsson, T., Siegbahn, A., Barratt, B. J., Becker, R. C., Himmelmann, A., Katus, H. A., Steg, P. G., Storey, R. F., Wallentin, L., on behalf of the PLATO Invest Tags: ASSOCIATION STUDIES ARTICLE Source Type: research
Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration
Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mi...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Chung, C., Puthanveetil, P., Ory, D. S., Lieberman, A. P. Tags: ARTICLES Source Type: research
Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation
Profilin 1 (PFN1) is an actin monomer-binding protein essential for regulating cytoskeletal dynamics in all cell types. Recently, mutations in the PFN1 gene have been identified as a cause of familial amyotrophic lateral sclerosis (ALS). The co-aggregation of PFN1 bearing mutations that cause ALS with TDP-43 (a key molecule in both sporadic and some familial forms of ALS), together with the classical TDP-43 pathology detected in post-mortem tissues of patients with autosomal dominant PFN1 mutation, imply that gain-of-toxic-function of PFN1 mutants is associated with the onset of ALS. However, it remains unknown how PFN1 mu...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Tanaka, Y., Nonaka, T., Suzuki, G., Kametani, F., Hasegawa, M. Tags: ARTICLES Source Type: research
Identification of consensus motifs associated with mitotic recombination and clinical characteristics in patients with paternal uniparental isodisomy of chromosome 11
Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in approximately 20% of patients with Beckwith–Wiedemann syndrome (BWS) and almost all pUPDs are segmental isodisomic pUPDs resulting from mitotic recombination at an early embryonic stage. A mechanism initiating a DNA double strand break (DSB) within 11p has been predicted to lead to segmental pUPD. Howeve...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Ohtsuka, Y., Higashimoto, K., Oka, T., Yatsuki, H., Jozaki, K., Maeda, T., Kawahara, K., Hamasaki, Y., Matsuo, M., Nishioka, K., Joh, K., Mukai, T., Soejima, H. Tags: ARTICLES Source Type: research
Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity
Low levels of the survival motor neuron (SMN) protein cause spinal muscular atrophy, the leading genetic disorder for infant mortality. SMN is ubiquitously expressed in various cell types and localizes in both the cytoplasm and the nucleus, where it concentrates in two subnuclear structures termed Cajal body (CB) and gems. In addition, SMN can also be detected in the nucleolus of neurons. Mechanisms that control SMN sorting in the cell remain largely unknown. Here, we report that the ubiquitin (Ub) ligase Itch directly interacts with and monoubiquitinates SMN. Monoubiquitination of SMN has a mild effect on promoting protea...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Han, K.-J., Foster, D., Harhaj, E. W., Dzieciatkowska, M., Hansen, K., Liu, C.-W. Tags: ARTICLES Source Type: research
A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma
We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lac...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Liu, C., Widen, S. A., Williamson, K. A., Ratnapriya, R., Gerth-Kahlert, C., Rainger, J., Alur, R. P., Strachan, E., Manjunath, S. H., Balakrishnan, A., Floyd, J. A., UK10K Consortium, Li, T., Waskiewicz, A., Brooks, B. P., Lehmann, O. J., FitzPatrick, D. Tags: ARTICLES Source Type: research
A critical period of vulnerability to adolescent stress: epigenetic mediators in mesocortical dopaminergic neurons
We report that 3-week (5–8 weeks of age) adolescent stress in combination with disrupted-in-schizophrenia 1 (Disc1) genetic risk elicits alterations in DNA methylation of a specific set of genes, tyrosine hydroxylase, brain-derived neurotrophic factor and FK506 binding protein 5. The epigenetic changes in the mesocortical dopaminergic neurons were prevented when animals were treated with a glucocorticoid receptor (GR) antagonist RU486 during social isolation, which implicates the role for glucocorticoid signaling in this pathological event. We define the critical period of GR intervention as the first 1-week period d...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Niwa, M., Lee, R. S., Tanaka, T., Okada, K., Kano, S.-I., Sawa, A. Tags: ARTICLES Source Type: research
Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the {gamma}-sarcoglycan-null mouse
In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in -sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: de Greef, J. C., Hamlyn, R., Jensen, B. S., O'Campo Landa, R., Levy, J. R., Kobuke, K., Campbell, K. P. Tags: ARTICLES Source Type: research
