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Molecular Therapy. Methods & Clinical Development

Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Zhongzhen Yi, Brooke L Prinzing, Felicia Cao, Stephen Gottschalk, Giedre Krenciute
Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissue. Building upon our previous findings in this area, we generated and evaluated a panel of EphA2-specific CARs. We demonstrate here that T cells expressing CD28...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Harrison C Brown, Philip M Zakas, Stephan N George, Ernest T Parker, H Trent Spencer, Christopher B Doering
Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Qizhen Shi
Gene therapy is an attractive approach for disease treatment. Since platelets are abundant cells circulating in blood with the distinctive abilities of storage and delivery and fundamental roles in hemostasis and immunity, they could be a unique target for gene therapy of diseases. Recent studies have demonstrated that ectopic expression of factor VIII (FVIII) in platelets under control of the platelet-specific promoter results in FVIII storage together with its carrier protein von Willebrand factor (VWF) in α-granules and the phenotypic correction of hemophilia A...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Joni Keto, Tanja Kaartinen, Urpu Salmenniemi, Johanna Castrén, Jukka Partanen, Arno Hänninen, Matti Korhonen, Kaarina Lähteenmäki, Maija Itälä-Remes, Johanna Nystedt
Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Shelley A Nass, Maryellen A Mattingly, Denise A Woodcock, Brenda L Burnham, Jeffrey A Ardinger, Shayla E Osmond, Amy M Frederick, Abraham Scaria, Seng H Cheng, Catherine R O'Riordan
The generation of clinical good manufacturing practices (GMP)-grade adeno-associated virus (AAV) vectors requires purification strategies that support the generation of vectors of high purity, and that exhibit a good safety and efficacy profile. To date, most reported purification schemas are serotype dependent, requiring method development for each AAV gene therapy product. Here, we describe a platform purification process that is compatible with the purification of multiple AAV serotypes. The method generates vector preparations of high purity that are enriched for capsids with full vector genomes, and that minimizes the fractional content of empty capsids...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Wannisa Khamaikawin, Saki Shimizu, Masakazu Kamata, Ruth Cortado, Yujin Jung, Jennifer Lam, Jing Wen, Patrick Kim, Yiming Xie, Sanggu Kim, Hubert Arokium, Angela P Presson, Irvin S Y Chen, Dong Sung An
Investigations of anti-HIV-1 human hematopoietic stem/progenitor cell (HSPC)-based gene therapy have been performed by HIV-1 challenge after the engraftment of gene-modified HSPCs in humanized mouse models. However, the clinical application of gene therapy is to treat HIV-1-infected patients. Here, we developed a new method to investigate an anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. First, humanized mice were infected with HIV-1. When plasma viremia reached >107 copies/mL 3 weeks after HIV-1 infection, the mice were myeloablated with busulfan and transplanted with anti-HIV-1 gene-modified CD34+ HSPCs transduced with a lentiviral vector expressing two short hairpin RNAs (shRNAs) against CCR5 and HIV-1 long terminal repeat (LTR), along with human thymus tissue under the kidney capsule...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Sylvie J Lavictoire, Alexander Gont, Lisa M Julian, William L Stanford, Caitlyn Vlasschaert, Douglas A Gray, Danny Jomaa, Ian A J Lorimer
The tumor suppressor PTEN is frequently inactivated in glioblastoma. PTEN-L is a long form of PTEN produced by translation from an alternate upstream start codon. Unlike PTEN, PTEN-L has a signal sequence and a tract of six arginine residues that allow PTEN-L to be secreted from cells and be taken up by neighboring cells. This suggests that PTEN-L could be used as a therapeutic to restore PTEN activity. However, effective delivery of therapeutic proteins to treat CNS cancers such as glioblastoma is challenging...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Gloriane Schnabolk, Nathaniel Parsons, Elisabeth Obert, Balasubramaniam Annamalai, Cecile Nasarre, Stephen Tomlinson, Alfred S Lewin, Bärbel Rohrer
Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Michael C Milone, Vijay G Bhoj
Adoptive cellular therapy using T cells with tumor specificity derived from either natural T cell receptors (TCRs) or an artificial chimeric antigen receptor (CAR) has reached late phase clinical testing, with two CAR T cell therapies achieving regulatory approval within the United States in 2017. The effective use of these therapies depends upon an understanding of their pharmacology, which is quite divergent from traditional small molecule or biologic drugs. We review the different types of T cell therapy under clinical development, the factors affecting cellular kinetics following infusion, and the relationship between these cellular kinetics and anti-cancer activity...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Henrieta Fraser, Niloufar Safinia, Nathali Grageda, Sarah Thirkell, Katie Lowe, Laura J Fry, Cristiano Scottá, Andrew Hope, Christopher Fisher, Rachel Hilton, David Game, Paul Harden, Andrew Bushell, Kathryn Wood, Robert I Lechler, Giovanna Lombardi
The concept of regulatory T cell (Treg)-based immunotherapy has enormous potential for facilitating tolerance in autoimmunity and transplantation. Clinical translation of Treg cell therapy requires production processes that satisfy the rigors of Good Manufacturing Practice (GMP) standards. In this regard, we report our findings on the implementation of a robust GMP compliant process for the ex vivo expansion of clinical grade Tregs, demonstrating the feasibility of this developed process for the manufacture of a final product for clinical application...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Beatriz Silva Lima, Mafalda Ascensão Videira
Since the human genome decoding, understanding and identification of genetic disturbances behind many diseases, including cancer, are intensively increasing. Scientific and technological advances in this area trigger the search for therapeutic (curative) approaches targeting the correction of gene disturbances. Gene therapy medicinal products (GTMPs) emerge in this context, bringing new challenges for their characterization. Compared to small molecules, biodistribution is fundamental to identifying target organs and anticipating safety and efficacy, may be integrated into safety and pharmacology studies, and may eventually be anticipated based on specificities of vectors and constructs...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Lindsay M Wallace, Nizar Y Saad, Nettie K Pyne, Allison M Fowler, Jocelyn O Eidahl, Jacqueline S Domire, Danielle A Griffin, Adam C Herman, Zarife Sahenk, Louise R Rodino-Klapac, Scott Q Harper
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Timothy K MacLachlan, Mark N Milton, Oliver Turner, Francis Tukov, Vivian W Choi, Jan Penraat, Marie-Hélène Delmotte, Lydia Michaut, Bruce D Jaffee, Chad E Bigelow
Retinitis pigmentosa is a form of retinal degeneration usually caused by genetic mutations affecting key functional proteins. We have previously demonstrated efficacy in a mouse model of RLBP1 deficiency with a self-complementary AAV8 vector carrying the gene for human RLBP1 under control of a short RLBP1 promoter (CPK850).1 In this article, we describe the nonclinical safety profile of this construct as well as updated efficacy data in the intended clinical formulation. In Rlbp1-/- mice dosed at a range of CPK850 levels, a minimum efficacious dose of 3 × 107 vg in a volume of 1 μL was observed...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Kayla A Quirin, Jason J Kwon, Arafat Alioufi, Tricia Factora, Constance J Temm, Max Jacobsen, George E Sandusky, Kim Shontz, Louis G Chicoine, K Reed Clark, Joshua T Mendell, Murray Korc, Janaiah Kota
Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg)...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Pasqualina Colella, Giuseppe Ronzitti, Federico Mingozzi
In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Olivier Humbert, Christopher W Peterson, Zachary K Norgaard, Stefan Radtke, Hans-Peter Kiem
Reactivation of fetal hemoglobin (HbF) is a promising approach for the treatment of β-hemoglobinopathies and the targeting of genes involved in HbF regulation is under intensive investigation. Here, we established a nonhuman primate (NHP) transplantation model to evaluate hematopoietic stem cell (HSC)-based gene editing strategies aimed at reactivating HbF. We first characterized the transient HbF induction to autologous HSC transplantation in pigtailed macaques, which was comparable in duration and amplitude to that of human patients...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Hongjie Wang, Maximilian Richter, Nikoletta Psatha, Chang Li, Jiho Kim, Jing Liu, Anja Ehrhardt, Susan K Nilsson, Benjamin Cao, Donna Palmer, Philip Ng, Zsuzsanna Izsvák, Kevin G Haworth, Hans-Peter Kiem, Thalia Papayannopoulou, André Lieber
We recently reported on an in vivo hematopoietic stem cell (HSC) gene therapy approach. It involves the subcutaneous injections of G-CSF/AMD3100 to mobilize HSCs from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating helper-dependent adenovirus vector system. HSCs transduced in the periphery homed back to the bone marrow, where they persisted long-term. However, high transgene marking rates found in primitive bone marrow HSCs were not reflected in peripheral blood cells...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Steven Q Le, Shih-Hsin Kan, Don Clarke, Valentina Sanghez, Martin Egeland, Kristen N Vondrak, Terence M Doherty, Moin U Vera, Michelina Iacovino, Jonathan D Cooper, Mark S Sands, Patricia I Dickson
Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l-iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Valentina Poletti, Fulvio Mavilio
Replication-defective retroviral vectors have been used for more than 25 years as a tool for efficient and stable insertion of therapeutic transgenes in human cells. Patients suffering from severe genetic diseases have been successfully treated by transplantation of autologous hematopoietic stem-progenitor cells (HSPCs) transduced with retroviral vectors, and the first of this class of therapies, Strimvelis, has recently received market authorization in Europe. Some clinical trials, however, resulted in severe adverse events caused by vector-induced proto-oncogene activation, which showed that retroviral vectors may retain a genotoxic potential associated to proviral integration in the human genome...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
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