Rapid progress in knowledge of the organization of the dog genome has facilit

ated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for several human diseases, such as Leber's congenital amaurosis 2-LCA2 (caused by a mutation of RPE65), X-linked retinitis pigmentosa (XLRP) caused by mutation RPGR, and achromatopsia caused by mutation of CNGB3. Promising results were also obtained for canine as follows: hemophilia A and B, mucopolysaccharidosis (MPS I, MPS IIIB, MPS VII,), leukocyte adhesion deficiency (CLAD) and muscular dystrophy (a counterpart of human Duchenne dystrophy). Present knowledge on molecular background of canine monogenic diseases and their successful gene therapies prove that dogs have an important contribution to preclinical studies.

The review appeared in March 18th online issue of J Appl Genet

-Mol Ther Methods Clin Dev. 2019 Dec 25;17:198-208. Immune Response Mechanisms against AAV Vectors in Animal Models. Martinot AT et al. College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA. Link: Abstract – Text

-J Neuromuscul Dis. 2019;6(4):421-451. The Dog Model in the Spotlight: Legacy of a Trustful Cooperation. Barthélémy I et al. École nationale vétérinaire d'Alfort, Maisons-Alfort, France Link: Abstract – Full Text

-Curr Gene Ther. 2015;15(6):531-40. Contemporary Animal Models For Human Gene Therapy Applications. Gopinath C et al. School of Biosciences and Technology, VIT University, Vellore - 632014, TN, India. Link: Abstract

Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection because of persistent covalently closed circular (ccc) DNA. CRISPR/Cas9-mediated specific cleavage of cccDNA is a potentially curative strategy for chronic hepatitis B (CHB). However, the CRISPR/Cas system inevitably targets integrated HBV DNA and induces double-strand breaks (DSBs) of host genome, bearing the risk of genomic rearrangement and damage. Taiwanese researchers have examined the utility of recently developed CRISPR/Cas-mediated base editors (BE) in inactivating HBV gene expression without cleavage of DNA. Candidate target sites of the spCas9-derived BE and its variants in HBV genomes were screened for generating nonsense mutations of viral genes with individual guide RNAs (gRNAs). SpCas9-BE with certain gRNAs effectively base-edited polymerase and surface genes and reduced HBV gene expression in cells harboring integrated HBV genomes, but induced very few indels. Interestingly, some point mutations introduced by base editing resulted in simultaneous suppression of both polymerase and surface genes. Finally, the episomal cccDNA was successfully edited by spCas9-BE for suppression of viral gene expression in an in vitro HBV infection system. In conclusion, Cas9-mediated base editing is a potential strategy to cure CHB by permanent inactivation of integrated HBV DNA and cccDNA without DSBs of host genome.

The results appeared in March 18th online issue of Mol Ther Nuc Acids

-Curr Opin HIV AIDS. 2020 Mar 5. Recent developments with advancing gene therapy to treat chronic infection with hepatitis B virus. Maepa MB et al. Health Sciences Faculty, University of the Witwatersrand, Johannesburg, South Africa. Link: Abstract

-Front Immunol. 2018 Sep 11;9:2080. Inhibition of HBV Expression in HBV Transgenic Mice Using AAV-Delivered CRISPR-SaCas9. Li H et al. Academy of Military Medical Sciences, Beijing, China Results / Comments : IThe results further confirm the potential of the CRISPR-Cas9 technique for use in hepatitis B gene therapy. Link: Abstract – Full Text

Chitosan (CS), a natural biopolymer, has been extensively explored for multiple applications including tissue engineering, gene therapy, bio-imaging and sewage treatment due to its abundant availability, intrinsic biocompatibility, biodegradability and tunable biological properties. Nevertheless, the actual use of CS is limited on account of its water-insolubility in physiological circumstances, which could be optimized by chemical modifications via active side groups. Etherification is one of the most widespread-used reactions to obtain water-soluble CS derivatives, such as hydroxybutyl CS (HBC). Hydroxybutyl CS (HBC), synthesized by grafting hydroxybutyl groups to the functional hydroxyl and amino groups of CS skeleton, has been demonstrated to possess superior biological properties over CS, especially satisfactory water solubility in neutral condition and reversible stimulus-responsive against the external thermo. Meanwhile, the unique characteristics of thermal sensitive "sol-gel" and "sol-micelle" transition have gained tremendous attention, which differ in heterogeneously and homogeneously synthesized HBC.

The review appeared in March 23rd online issue of Biomacromolecules

Related Informations / Publications

-Int J Mol Sci. 2019 Nov 16;20(22). Synthesis, Bioapplications, and Toxicity Evaluation of Chitosan-Based Nanoparticles. Rizeq BR et al. College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar

Results/Comments: This article presents a comprehensive overview of recent

advances in chitosan derivatives and nanoparticle synthesis, as well as emerging applications in medicine, tissue engineering, drug delivery, gene therapy, and cancer therapy.  Link: Abstract – Full Text

-Molecules. 2019 Oct 17;24(20). Biodegradable Polymers for Gene Delivery. Thomas TJ et al. Rutgers Robert Wood Johnson Medical School, KTL N102, 675 Hoes Lane, Piscataway, NJ 08854, USA. Link: Abstract – Full Text

Chimeric antigen receptor (CAR)-T-cell therapy has sparked a wave of optimism in hematological malignancies, reflected by the successful results of early clinical trials involving patients with pre-B-cell acute lymphoblastic leukemia, B-cell lymphomas and multiple myeloma. CAR-T-cell therapy is considered to be a novel immunotherapy treatment that has the potential for curing certain hematological cancers. However, as use of CAR-T-cell therapy has grown, new challenges have surfaced. These challenges include the process of manufacturing the CAR-T cells, the mechanisms of resistance that underlie disease relapse, adverse effects and cost. This review describes the published results of clinical trials and expected developments to overcome CAR-T resistance.

The review appeared in March 21st online issue of J Investig Med

-Clin Immunol. 2020 Mar 10;214:108382. Use of CAR-T cell therapy, PD-1 blockade, and their combination for the treatment of hematological malignancies. Song W et al. Academy of Medical Sciences of Zhengzhou University, 450052 Zhengzhou City, Henan Province, China. Link: Abstract

-Oncologist. 2020 Feb;25(2):e321-e327. The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma. Ali S et al. European Medicines Agency, Amsterdam, The Netherlands. Link: Abstract – Full Text

-Cancers (Basel). 2020 Jan 3;12(1). Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment. Titov A et al. Kazan Federal University, 420008 Kazan, Russia. Link: Abstract – Full Text

-Curr Med Sci. 2019 Dec;39(6):874-882. CAR T Cell Therapy for Hematological Malignancies. Yang X et al. Huazhong University of Science and Technology, Wuhan, 430030, China. Link: Abstract

-Proc Natl Acad Sci U S A. 2020 Mar 10. Potent CRISPR-Cas9 inhibitors from Staphylococcus genomes. Watters KE et al. University of California, Berkeley, CA 94720, USA. Link: Abstract – Full Text

-Genome Biol. 2020 Feb 26;21(1):51. Allosteric inhibition of CRISPR-Cas9 by bacteriophage-derived peptides. Cui RY et al. ShanghaiTech University, Shanghai, 201210, China Results/Comments: G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9

Link: Abstract – Full Text

-Cell Host Microbe. 2020 Feb 12;27(2):189-198.e6. Exploitation of the Cooperative Behaviors of Anti-CRISPR Phages. Chevallereau A et al. University of Exeter, Cornwall Campus, Penryn TR10 9EZ, UK. Link: Abstract

Related Informations / Publications

-MAR 2020 : Pfizer and BioNTech to Co-develop Potential COVID-19 Vaccine

Results/Comments: The collaboration aims to accelerate development of BioNTech’s potential first-in-class COVID-19 mRNA vaccine program, BNT162, which is expected to enter clinical testing by the end of April 2020. Link: Press Release

-MAR 2020: Moderna Announces First Participant Dosed in NIH-led Phase 1 Study of mRNA Vaccine (mRNA-1273) Against Novel Coronavirus

Results/Comments: Moderna announced on March 16th that the first participant has been dosed in the Phase 1 study of the Company’s mRNA vaccine (mRNA-1273) against the novel coronavirus (SARS-CoV-2). This Phase 1 study is being conducted by the National Institutes of Health (NIH) under its own Investigational New Drug (IND) application. Link: Press Release

-MAR 2020 : CureVac focuses on the development of mRNA-based coronavirus vaccine to protect people worldwide. Link: Press Release

-Eur Rev Med Pharmacol Sci. 2020 Feb;24(4):2006-2011. COVID-19 (Novel Coronavirus 2019) - recent trends. Kannan S et al. The Maldives National University, Male', Maldives Results/Comments: This mini-review aims at investigating the most recent trend of COVID-19. Link: Abstract

-J Neuromuscul Dis. 2020;7(1):1-13. Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. Schorling DC et al. University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Results/Comments: Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.

Link: Abstract – Full Text

-Pediatr Neurol. 2019 Nov;100:3-11. From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1. Al-Zaidy SA et al. Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA

Link: Abstract – Full Text

-Drugs. 2019 Jul;79(11):1255-1262. Onasemnogene Abeparvovec: First Global Approval. Hoy SM. Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

Results/Comments: This article summarizes the milestones in the development of onasemnogene abeparvovec leading to this first approval for the treatment of paediatric patients aged < 2 years with SMA and bi-allelic mutations in SMN1. Link: Abstract

-DEC 2019 : ImCheck Raises $53 Million Series B to Advance Clinical Pipeline of Novel Gamma Delta T-Cell-Focused Antibodies for Cancer and Autoimmune Diseases

Results/Comments: Bpifrance and Pfizer Ventures co-led international investor syndicate. Link: Press Release

-J Immunother Cancer. 2019 Mar 12;7(1):69. Evaluating in vivo efficacy - toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells. Johanna I et al. University Medical Center Utrecht, Utrecht, The Netherlands. Link: Abstract – Full Text

-Front Immunol. 2018 Jul 11;9:1601. New Insights Into the Regulation of γδ T Cells by BTN3A and Other BTN/BTNL in Tumor Immunity. Blazquez JL et al. Immunity & Cancer, Institut Paoli-Calmettes; Aix-Marseille Université UM105, CNRS UMR 7258, Marseille, France

Results/Comments: Antibodies targeting BTN3A have shown in vitro and in vivo efficacy in human tumors such as acute myeloid leukemia or pancreatic cancer

Link: Abstract – Full Text

Silence Therapeutics announced on March 25th a strategic collaboration with AstraZeneca to discover, develop and commercialize small interfering RNA (siRNA) therapeutics for the treatment of Cardiovascular, Renal, Metabolic and Respiratory diseases. The collaboration draws on Silence’s extensive experience as a leader in the discovery, development and delivery of siRNA therapeutics together with AstraZeneca’s industry leading expertise in disease biology and target identification with the aim of developing first-in-class and differentiated therapeutics to address significant unmet need. AstraZeneca will make an upfront cash payment of $60 million and an equity investment of $20 million in Silence. The parties anticipate initiating work on five targets within the first three years of the collaboration, with AstraZeneca having the option to extend the collaboration to a further five targets. Silence will harness its established GalNAc-siRNA platform to inhibit liver expressed gene targets and the companies will collaborate to achieve targeted delivery of siRNA molecules to other tissues including heart, kidney and lung. Delivery of siRNA molecules to the liver hepatocytes is an established approach; targeted delivery to these other tissue types represents a new and compelling opportunity to treat Cardiovascular, Renal, Metabolic and Respiratory diseases. For further information,

-JAN 2020: Silence Therapeutics Announces Business Update

Results/Comments: The Company is encouraged by the growing prominence of RNAi technology, as evidenced by the approval of Alnylam’s Givosiran, and a number of significant partnerships and transactions in the RNAi space, including agreements between Dicerna Pharmaceuticals and Novo Nordisk, the $9.7 billion acquisition of The Medicines Company by Novartis and Silence’s own collaboration with Mallinckrodt Pharmaceuticals to develop and commercialise RNAi therapeutics for complement mediated diseases. Link: Press Release

-JUL 2019 : Silence Therapeutics and Mallinckrodt announce collaboration to develop and commercialize RNAi therapeutics for complement-mediated diseases Results/Comments: Under the terms of the agreement, Mallinckrodt will obtain an exclusive worldwide license to Silence’s C33 complement asset, SLN500, with options to license up to two additional complement-targeted assets in Silence’s preclinical complement-directed RNAi development program. Link: Press Release

Horama, a French biotechnology company focusing on gene therapy for the treatment of rare genetic diseases in ophthalmology, announced on March 18th an exclusive licensing agreement with the Leiden University Medical Center (LUMC) for global rights to a gene therapy program to treat the Inherited Retinal Dystrophy associated with pathogenic CRB1 gene mutations, a rare but devastating ophthalmic condition leading to blindness. Under the agreement, Horama will receive an exclusive worldwide license to certain patent rights and know-how for the drug candidate (referenced as HORA-001). In return for these rights, LUMC will receive an undisclosed upfront payment, milestone payments and royalties on net sales of products. Horama shall be responsible to bring the gene therapy to market with completion of the non-clinical and clinical studies. Based on current timelines, and subject to regulatory review, Horama expects initiating a Phase I/II clinical study with HORA-001 in 2023.

-Br J Ophthalmol. 2019 Oct 19. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy. Xu K et al. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. Link: Abstract.

-Adv Exp Med Biol. 2019;1185:251-255. The Enigma of CRB1 and CRB1 Retinopathies. Ray TA et al. Duke University School of Medicine, Durham, NC, USA

Results/Comments: The purpose of this review is to summarize what is known regarding CRB1 and highlights information outstanding. Link: Abstract

-SEP 2018: Horama completes its 22.5 million euros “Series B” financing round Results/Comments: This completes the “Series B” fundraising of Horama, which was initiated in October 2017 through participation of 4 new investors (Kurma Partners, Fund+, Pontifax and Idinvest), joined by the company’s historical investors (Omnes Capital, GO Capital, and Sham Innovation Santé/Turenne). Link: Press Release

At present, pay for prescription models are insufficient at containing costs and improving access to medicines. Subscription financing through tenders, licensing fees and unrestricted or fixed volumes can benefit stakeholders across the supply chain. Pharmaceutical manufacturers can reduce the need for marketing expenses and gain certainty in revenue. This will decrease costs, improve predictability in budget expenditure for payers and remove price as a barrier of access from patients. Inherently, low- and middle-income countries lack the purchasing power to leverage price discounts through typical price arrangements. These markets can realise substantial savings for branded and generic medicines through subscription financing. Procuring of on-patent and off-patent drugs requires separate analysis for competition effects, the length of contract and encouraging innovation in the medicine pipeline. Prices of competitive on-patent medicines and orphan drugs can be reduced through increased competition and volume. Furthermore, pooling expertise and resources through joint procurement has the potential for greater savings. Incentivising research and development within the pharmaceutical industry is essential for sustaining a competitive market, preventing monopolies and improving access to expensive treatments.

The analysis appeared in the March issue of Health Econ Policy Law 

-Soc Hist Med. 2019 Aug;32(3):609-630. Orphans in the Market: The History of Orphan Drug Policy. Mikami K.

Results /Comments : The paper makes visible an alternative trajectory that existed for a while in the United Kingdom but was eventually abandoned in order to help the biotechnology industry grow in the context of an increasingly integrated European drug market. Link: Abstract– Full Text

-Eur J Clin Pharmacol. 2018 Jul;74(7):895-902. Policies and availability of orphan medicines in outpatient care in 24 European countries. Sarnola K et al. Kuopio Campus, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland Results/Comments: Most European countries had not implemented pricing and reimbursement policies specific to orphan medicines. The availability of orphan products varied between countries Link: Abstract