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Rare forms of interstitial lung disease
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
There are other lipid storage disorders in which the lung may become involved. These include Fabry disease, Farber disease, gangliosidoses, Krabbe disease, Wolman disease and metachromatic leukodystrophy (150,154,155). However, these disorders are rarer, and pulmonary involvement has been incompletely described or is overshadowed by extra-pulmonary manifestations.
Accident and Emergency
Published in Nagi Giumma Barakat, Get Through, 2006
25-28. For each of the following scenarios, select the investigation most likely to give a definite diagnosis from the list below: A 2-year-old child with left eye glaucoma is developmentally delayed and has multiple seizure types. His renal scan shows small cortical cystic lesions. The EEG shows hypsarrhyth-mia. He is on vigabatrin and topiramate.A 7-day-old baby girl has been diagnosed with Horner’s syndrome. She is unable to move her right arm. Delivery was difficult, with shoulder dystocia and required forceps. No fractures are noted, and a cranial CT scan is reported as normal.An 11-year-old boy has a history of blurred vision in both eyes, the left more than the right, and double vision when looking to either side. Fundus examination shows papil-loedema more on the left. A cranial MRI is normal as in a VEP. A DNA study for Farber’s disease is normal.A 4-year-old girl has a history of clumsiness and frequently falls over. Her foot arch is very high, with reduced reflexes at her ankles. Her bladder and bowel control are good. She finds it difficult to rise from a sitting to a standing position and has to use her arms to raise her body. Peroneal nerve conduction and cranial MRI are normal. Creatinine kinase is 250 mmol/l.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
There are also groups investigating alternative uses of well-characterized cell and gene therapy protocols to optimize brain delivery. One such approach aims to deliver LV-modified HSCs directly into the brain. Human CD34+ HSCs injected intracerebroventricularly into an immunodeficient arylsulfatase A knockout mouse model of MLD resulted in robust, rapid engraftment of donor cells in the brain. These cells differentiated to display similar morphology, surface markers, and transcriptional profile as that of adult microglia, and actively secreted arylsulfatase A in the brain [99]. Alternatively, novel cellular delivery vehicles can be developed, for example neural progenitor cells (NPCs) differentiated from patient-derived induced pluripotent stem cells (iPSCs) [133,134]. Unmodified fetal NPCs have been tested for safety in a clinical trial treating CLN1/2 (NCT00337636) [134]. Surgery, immunosuppression, and cell transplantation were well tolerated with no adverse events being attributed to the donor cells [134]. A patient’s own NPCs could be engineered to overexpress a normal version of a deficient or dysfunctional enzyme contributing to cross-correction and, importantly, to neural regeneration [133]. Similarly, other stem cell compartments for appropriately affected tissues could be engineered for therapy, for example mesenchymal stem cells (MSCs) [135]. Conversely, genetically augmented ‘mature’ cells can also be used as cell therapies. Differentiated hematopoietic cells naturally circulate through their blood and lymphatic system niche and could be used to widely spread therapeutic enzyme. Our group is investigating using differentiated rapamycin-resistant T cell ‘micropharmacies’ to deliver therapeutic transgene products systemically for the treatment of LSDs [136]. T cells obtained from peripheral blood without a mobilization protocol, expanded exponentially ex vivo, and cultured with rapamycin exhibit an anti-apoptotic, pro-engraftment, phenotype [136]. These resulting T Rapa cells engraft with reduced host conditioning [137]. T Rapa cells have been manufactured from peripheral blood of affected Fabry disease patients, transduced with the LV vector used in the NCT02800070 Fabry clinical trial, expanded, and xenografted into NOD/SCID/Fabry mice where they secrete α-galactosidase A in the absence of stimulation [136]. This T Rapa ‘micropharmacy’ strategy is also being evaluated by us for the secretion of proteins relevant to other LSDs including Gaucher disease, Farber disease, and Pompe disease.