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“Kidney in a Dish” Organoids for PKD
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Nelly M. Cruz, Benjamin S. Freedman
Two decades after PKD1 and PKD2 were first discovered, how these genes normally function to prevent cystogenesis is still not fully understood.1,2 A major barrier to deciphering PKD mechanistically has been a lack of human cellular models that faithfully recapitulate PKD-specific cystogenesis from tubules. Rodent and other vertebrate models replicate certain features of PKD, but do not fully genocopy or phenocopy human PKD or its treatment.3,4 Animal models are furthermore highly complex, placing constraints on experimental approaches and throughput. In vitro, polarized epithelial cells in three-dimensional cultures can form hollow spheroids, sometimes called “cysts,” but such structures arise even in nonmutant cells and are therefore not PKD-specific.5,6
Keeping it in the family: the case for considering late-onset combined immunodeficiency a subset of common variable immunodeficiency disorders
Published in Expert Review of Clinical Immunology, 2018
Rohan Ameratunga, Yeri Ahn, Anthony Jordan, Klaus Lehnert, Shannon Brothers, See-Tarn Woon
The fifth argument for not separating the two conditions is the substantial genetic overlap between these conditions (genocopy, locus heterogeneity). Differing genetics was one of the most important arguments for separating these two conditions. Recent data however show there is considerable phenotypic overlap between mutations which cause LOCID vs. those causing CVID-like disorders, including ICOS, NFKB1, NFKB2, LRBA, PI3KD, and CTLA4 [22,34–40]. Each of these references describes patients with CIDs caused by these mutations, often within the same family, while the majority have ‘typical’ CVID-like disorders. Therefore, the family presented here is not unique. As the genetic basis for other CVID patients is identified, the distinction between CVID/CVID-like disorders and LOCID will become even more blurred. Given these new discoveries, genocopy is now the strongest argument for not separating LOCID from CVID and CVID-like disorders.
Advances in emerging therapeutics for oculopharyngeal muscular dystrophy
Published in Expert Opinion on Orphan Drugs, 2018
Pradeep Harish, George Dickson, Alberto Malerba
Gene therapy is currently among the most promising strategies for the treatments of rare neuromuscular diseases, and substantial advancements have been shown in clinical applications for Myotubular myopathy, Spinal muscular atrophy, and Duchenne muscular dystrophy. A gene therapy treatment based on silencing the mutated PABPN1 and replacing it with normal PABPN1 has been tested in the A17 mouse model. Notably, this mouse is characterized by substantial overexpression of expanded PABPN1 which does not mimic the native balance of normal and mutated PABPN1 naturally present in heterozygous patients. Therefore we cannot exclude that in human condition the simple overexpression of normal PABPN1 may not be sufficient to improve the disease. It would be interesting to verify such gene addition approach on the recently generated mouse model that represents a genocopy of the human condition. The silence and replacement gene therapy approach based on the single vector BB-301 is currently under toxicological study in sheep whose anatomy for pharyngeal muscles closely mimic the human one. A clinical trial based on local intramuscular injection of such vector is planned to start in 2019. While the local gene therapy approach holds exciting expectations, more work is needed to assess if a systemic administration is safe and effective. Indeed, while the current gene therapy systemic clinical trials for neuromuscular diseases are based on gene replacement only, the current vector for OPMD also includes a dual shRNA cassette to knock down mutated PABPN1 that may potentially have detrimental effects if expressed in off-target organs. However, the embedding of shRNAs into a microRNA backbone is expected to produce a few predominant, highly active species of siRNA compared to a larger set of sequences as happens with the typical pol III-driven shRNA cassette and this should reduce the potential off-target effects. Furthermore, the use of a muscle-specific promoter to drive the shRNA expression reduces the risk of microRNA pathway overloading and de-targets the expression from non-muscle tissues making the vector safer.