Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, characterized by deficient IDUA enzyme production and storage of glycosaminoglycans in tissues. Currently, therapeutic strategies approved have shown an improvement in quality of life of patients, but the majority of severe symptoms including cognitive and skeletal alterations persist. Gene therapy aimed to correct the genetic defect holds promise. Indeed, preclinical results show that it may be possible to develop a gene therapy strategy that may overcome the present limitations. In this review, authors review studies involving gene therapy for MPS I in the last years and highlight the most promising approaches. Authors review main studies involving gene therapy and genome editing for MPS I in the last 2–3 decades, from the initial in vitro studies up to the first clinical trials, and prospect what the future may hold for this technology in this disease. Among all strategies studied, viral gene therapy and genome editing are being applied in clinical trials. Some of the results are inconclusive while scaling the process from animal models to human. The key for better outcomes relies on giving patients a proper therapy.

The review appeared in January 29th online issue of Exp Opin Orphan Drugs

-Int J Mol Sci, Online ahead of print, Jan 13th, 2020. Genome Editing for Mucopolysaccharidoses. Poletto et al. Hospital de Clinicas de Porto Alegre, Porto Alegre 90035-007, Brazil

Results / Comments: The development of new genome editing platforms and the variety of genetic modifications possible with each tool provide potential applications of genome editing for mucopolysaccharidoses, which vastly exceed the potential of current approaches. Link: Abstract

- Gene Ther, Online ahead of print, Dec 19th, 2019. Neonatal Nonviral Gene Editing With the CRISPR/Cas9 System Improves Some Cardiovascular, Respiratory, and Bone Disease Features of the Mucopolysaccharidosis I Phenotype in Mice. Schuh et al. Hospital de Clinicas de Porto Alegre, R. Ramiro Barcelos 2350, 90035-903, Porto Alegre, RS, Brazil. Link: Abstract

-Handb Exp Pharmacol, Online ahead of print, Aug 27th, 2019. Current and Emerging Therapies for Mucopolysaccharidoses. Lagler FB. Paracelsus Medical University, Salzburg, Austria. Link: Abstract

In a recent publication, British researchers described retinal reconstruction and restoration of visual function in heritably blind mice missing the rhodopsin gene using a novel method of ex-vivo gene therapy and cell transplantation. Photoreceptor precursors with the same chromosomal genetic mutation, were treated ex vivo using minicircle DNA, a non-viral technique that does not present the packaging limitations of adeno-associated virus (AAV) vectors. Following transplantation, genetically-modified cells reconstructed a functional retina and supported vision in blind mice harboring the same founder gene mutation. Gene delivery by Minicircles, showed comparable long-term efficiency to AAV in delivering the missing gene, representing the first non-viral system for robust treatment of photoreceptors. This important proof-of-concept finding provides an innovative convergence of cell and gene therapies for the treatment of hereditary neurodegenerative disease and may be applied in future studies towards ex vivo correction of patient-specific cells to provide an autologous source of tissue to replace lost photoreceptors in inherited retinal blindness. This is the first report using minicircles in photoreceptor progenitors and the first to transplant corrected photoreceptor precursors to restore vision in blind animals. The results appeared in January 28th online issue of Mol Ther.

Related Informations / Publications

-Curr Gene Ther. 2019;19(5):318-329. Nano-enhanced Optical Gene Delivery to Retinal Degenerated Mice. Batabyal et al. Nanoscope Technologies LLC, 1312 Brown Trail, Bedford, TX, 76022, USA. Link: Abstract

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Clinical management of children with PAH is particularly challenging due to increased complexity of disease etiology and clinical presentation, as well as the lack of data from pediatric-specific clinical trials. In children, PAH often develops in association with congenital heart disease (APAH-CHD) and other developmental disorders. Emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 35% of pediatric-onset idiopathic PAH (IPAH) compared to ∼11% of adult-onset IPAH. De novo variants are the most frequent monogenetic cause of PAH in children, likely contributing to ∼15% of all cases. Rare deleterious variants in bone morphogenetic protein receptor 2 (BMPR2) contribute to pediatric-onset IPAH and familial PAH with similar frequency as adult-onset disease but rarely explain APAH cases. Rare deleterious variants in developmental genes - including T-box 4 containing protein (TBX4), SRY-related HMG box transcription factor (SOX17), and other genes requiring confirmation in larger cohorts - are emerging as important contributors to pediatric-onset disease.

The review appeared in January 29th online issue of Chest

Related Informations / Publications

-Br J Pharmacol. 2020 Jan 24. doi: 10.1111/bph.15000. Tetramethylpyrazine, a Promising Drug for Treatment of Pulmonary Hypertension. Chen et al. The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

Results / Comments: The results suggest that TMP is potentially a novel, potential and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379). Link: Abstract

-Paediatr Drugs. 2020 Jan 21. doi: 10.1007/s40272-019-00374-2. Drug Treatment of Pulmonary Hypertension in Children. Avitabile et al. Children's Hospital of Philadelphia, Philadelphia, PA, USA

Results / Comments: The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children. Link: Abstract

-Pediatr Pulmonol. 2020 Jan 9. doi: 10.1002/ppul.24637. Genes that drive the pathobiology of pediatric pulmonary arterial hypertension. Welch et al. Columbia University Irving Medical Center, New York, New York, USA Link: Abstract

GM2-gangliosidosis are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease, TS) or HEXB (Sandhoff disease, SD) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aimed to clarify the natural history of adult patients with GM2-gangliosidosis. Researchers retrospectively described 12 patients from a French cohort and 45 patients from the literature. They concluded that improved knowledge of GM2-gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies.

The results appeared in January 29th online issue of Ann Neurol

Related Informations / Publications

-Gene Ther, Online ahead of print, Jan 02nd 2020. A Novel Gene Editing System to Treat Both Tay-Sachs and Sandhoff Diseases. Ou et al. Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA. Link: Abstract

-Neurobiol Dis. 2020 Feb;134:104667. Novel bicistronic lentiviral vectors correct β-Hexosaminidase deficiency in neural and hematopoietic stem cells and progeny: implications for in vivo and ex vivo gene therapy of GM2 gangliosidosis. Ornaghi et al. IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy

Results / Comments: Careful assessment of the safety and therapeutic potential of these bicistronic LVs in the SD murine model will pave the way to the clinical development of LV-based gene therapy for GM2 gangliosidosis. Link: Abstract - Full Text

Duchenne muscular dystrophy animal models for high-throughput drug discovery and precision medicine

Duchenne muscular dystrophy (DMD) is an X-linked handicapping disease due to the loss of an essential muscle protein dystrophin. Dystrophin-null animals have been extensively used to study disease mechanisms and to develop experimental therapeutics. Despite decades of research, however, treatment options for DMD remain very limited. High-throughput high-content screening and precision medicine offer exciting new opportunities. Here, the authors review animal models that are suitable for these studies. Non-mammalian models (worm, fruit fly, and zebrafish) are particularly attractive for cost-effective large-scale drug screening. Several promising lead compounds have been discovered using these models. Precision medicine for DMD aims at developing mutation-specific therapies such as exon-skipping and genome editing. To meet these needs, models with patient-like mutations have been established in different species. Models that harbor hotspot mutations are very attractive because the drugs developed in these models can bring mutation-specific therapies to a large population of patients. Humanized hDMD mice carry the entire human dystrophin gene in the mouse genome. Reagents developed in the hDMD mouse-based models are directly translatable to human patients. The review appeared in January 30th online issue of Expert Opin Drug Discov

-Front Bioeng Biotechnol. 2019 Nov 29;7:373. Biomaterials and Advanced Biofabrication Techniques in hiPSCs Based Neuromyopathic Disease Modeling. Sun et al. The Chinese University of Hong Kong, Hong Kong, China

Results / Comments: In this review, researchers highlight the biomaterials and fabrication technologies used in human iPSC-based tissue engineering to model neuromyopathic diseases, particularly those with genetic mutations, such as Duchenne Muscular Dystrophy, Congenital Heart Diseases (CHD) and Alzheimer's disease (AD) Link: Abstract - Full Text

-Cells. 2019 Jan 3;8(1). pii: E20. iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies. Ortiz-Vitali et al. The University of Texas Health Science Center at Houston, Houston, TX 77030, USA

Link: Abstract - Full Text

-JAN 2019: Orchard Therapeutics Announces FDA Granted Orphan Drug Designation for OTL-102 for the Treatment of X-linked Chronic Granulomatous Disease (X-CGD)

Link: Press Release

-Hum Gene Ther Clin Dev. 2018 Jun;29(2):69-79. Non-Clinical Efficacy and Safety Studies on G1XCGD, a Lentiviral Vector for Ex Vivo Gene Therapy of X-Linked Chronic Granulomatous Disease. Brendel C et al. Institute for Tumor Biology and Experimental Therapy , Georg-Speyer-Haus, Frankfurt, Germany

Results / Comments: These studies paved the way for the approval of clinical trials in Europe and in the United States for the treatment of XCGD patients with G1XCGD gene-modified autologous hematopoietic cells. Link: Abstract

-Sci Transl Med. 2017 Jan 11;9(372). CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. De Ravin SS et al. National Institutes of Health, Bethesda, MD 20892, USA. Link: Abstract 

-StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–2019 Nov 15. Leukocyte Adhesion Deficiency. University of the West Indies, Jamaica. Link: Abstract

-DEC 2019 : Rocket Pharmaceuticals Announces Preliminary Data from Phase 1/2 Trial of RP-L201 for Leukocyte Adhesion Deficiency-I. Link: Press Release

-J Allergy Clin Immunol Pract, 6 (4), 1418-1420.e10, Jul-Aug 2018. Leukocyte Adhesion deficiency-I: A Comprehensive Review of All Published Cases. Novoa et al. Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain

Link: Abstract

-JAN 2018: Rocket Pharmaceuticals and Inotek Pharmaceuticals Complete Merger Transaction. Link: Press Release

Related Informations / Publications

-MMolecules, Online ahead of print, Jan 17th, 2020. Trypanocidal Activity of Flavanone Derivatives. Diogo et al. Campus Universitário Morro do Cruzeiro, Ouro Preto 35400-000, MG, Brazil Results / Comments : The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole (Roche). Link: Abstract

- Int J Parasitol Drugs Drug Resist, Online ahead of print, Dec 10th, 2019. Current Trends in the Pharmacological Management of Chagas Disease. Ribeiro et al. Faculty of Medicine, University of Brasilia, Brasilia, Federal District, Brazil. Link: Abstract

-MAR 2019: Bayer's Phase III Clinical Trial Of Nifurtimox In Pediatric Patients With Chagas Disease Meets Primary Endpoint. Link: PR Newswire

Following the release of the framework for the Real-World Evidence (RWE ) Program, the FDA is actively evaluating and exploring ways to optimize the utility of real-world data (RWD) and RWE to support regulatory decision making. For rare conditions, conducting traditional randomized clinical trials may not always be feasible, and RWD and RWE have played and will continue to play an important role. Researchers have used three case examples-cerliponase alfa, asfotase alfa, and uridine triacetate-to illustrate how RWD from disease registries, medical records with chart review, and literature, respectively, have been used to generate RWE to support regulatory decisions for selected rare diseases. These examples highlight the need for improving data reliability and quality in existing data to expand use of RWD and RWE beyond "hard endpoints" and standardizing data collection for outcome measures in patient registries to expand its utility. They also discuss a recent FDA guidance for using RWE in supporting rare disease drug development, including its recommendations about using natural history studies as external control groups for single-arm interventional trials. The external control group needs to be comparable with the treated group. Selection bias and confounding are major concerns because of lack of randomization and unrecognized baseline differences. The analysis appeared in January 30th online issue of Pharmacoepidemiol Drug Saf

-JAMA. 2020 Jan 14;323(2):164-176. FDA Approval and Regulation of Pharmaceuticals, 1983-2018. Darrow et al. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA Results / Comments : The FDA funding needed to implement and manage these programs has been addressed by expanding industry-paid user fees. The FDA has increasingly accepted less data and more surrogate measures, and has shortened its review times Link: Abstract

-BMJ Open. 2019 Oct 10;9(10):e028634. Application of orphan drug designation to cancer treatments (2008-2017): a comprehensive and comparative analysis of the USA and EU. Vokinger et al. Institute of Law, University of Zurich, Zurich, Switzerland

Link: Abstract - Full Text

-Hosp Pharm. 2019 Oct;54(5):283-284. The Orphan Drug Act: An Appropriate Approval Pathway for Treatments of Rare Diseases? Gabay M. The University of Illinois at Chicago, USA. Link: Abstract