Research

Gene therapy for primary immune deficiencies: a Canadian perspective.

Allergy Asthma Clin Immunol. 2017;13:14

Authors: Xu X, Tailor CS, Grunebaum E

Abstract
The use of gene therapy (GT) for the treatment of primary immune deficiencies (PID) including severe combined immune deficiency (SCID) has progressed significantly in the recent years. In particular, long-term studies have shown that adenosine deaminase (ADA) gene delivery into ADA-deficient hematopoietic stem cells that are then transplanted into the patients corrects the abnormal function of the ADA enzyme, which leads to immune reconstitution. In contrast, the outcome was disappointing for patients with X-linked SCID, Wiskott-Aldrich syndrome and chronic granulomatous disease who received GT followed by autologous gene corrected transplantations, as many developed hematological malignancies. The malignancies were attributed to the predilection of the viruses used for gene delivery to integrated at oncogenic areas. The availability of safer and more efficient self-inactivating lentiviruses for gene delivery has reignited the interest in GT for many PID that are now in various stages of pre-clinical studies and clinical trials. Moreover, advances in early diagnosis of PID and gene editing technology coupled with enhanced abilities to generate and manipulate stem cells ex vivo are expected to further contribute to the benefit of GT for PID. Here we review the past, the present and the future of GT for PID, with particular emphasis on the Canadian perspective.

PMID: 28261277 [PubMed]

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Systemic abnormalities associated with retinal vein occlusion in young patients.

Clin Ophthalmol. 2017;11:441-447

Authors: Sinawat S, Bunyavee C, Ratanapakorn T, Sinawat S, Laovirojjanakul W, Yospaiboon Y

Abstract
OBJECTIVES: To study the systemic abnormalities associated with retinal vein occlusion in patients aged ≤50 years with a particular emphasis on atherosclerotic diseases and thrombophilic disorders.
METHODS: Medical charts of patients, aged ≤50 years whose diagnoses were retinal vein occlusions during the period 1995-2015 were retrospectively reviewed. The primary outcome was the number of systemic abnormalities associated with these patients. Secondary outcomes included types of retinal vein occlusion and sites of occlusion.
RESULTS: Atherosclerotic diseases were the most common systemic abnormalities associated with retinal vein occlusion and accounted for 55.1% of the patients in the study. Hypertension in 27.55%, diabetes mellitus in 16.33%, and 5.1% with dyslipidemia were noted. The number of thrombophilic disorders seemed to be less than expected and were noted in only 5.1%. Other systemic abnormalities included viral hepatitis infection, systemic lupus erythematosus, and acquired immunodeficiency syndrome. Oral contraceptives were used by some patients.
CONCLUSION: Atherosclerotic diseases remained the most commonly associated systemic diseases in the majority of these patients. Approach to these patients should include a screening for hypertension, diabetes mellitus, and lipid abnormalities. Thrombophilia should also be considered where no obvious atherosclerotic diseases are found or if the patient is <40 years old, a history of thrombosis or a family history of thrombosis is possible.

PMID: 28260858 [PubMed – in process]

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Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS.

Mol Genet Metab. 2017 Feb 27;:

Authors: Bryan MM, Tolman NJ, Simon KL, Huizing M, Hufnagel RB, Brooks BP, Speransky V, Mullikin JC, Gahl WA, Malicdan MC, Gochuico BR

Abstract
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7.
RESULTS: A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [NM_032122.4: c.307C>T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient’s dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control.
CONCLUSIONS: Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient’s markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.

PMID: 28259707 [PubMed – as supplied by publisher]

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Novel insight into Chronic Inflammatory Demyelinating Polineuropathy in APECED syndrome: molecular mechanisms and clinical implications in children.

Ital J Pediatr. 2017 Jan 19;43(1):11

Authors: Valenzise M, Aversa T, Salzano G, Zirilli G, De Luca F, Su M

Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE gene mutation. It is characterized by the association of multiple autoimmune diseases, with a classical triad including chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. Its clinical spectrum has significantly enlarged in the last years with the apparence of new entities. One of these novel manifestations is the chronic inflammatory demyelinating polineuropathy (CIDP), that is characterized by involvement of peripheral nervous system, with nerve demyelination, progressive muscular weakness of both arms and legs and sensory loss. The identification of myelin protein zero as an important autoantigen (Ag) in CIDP may suggest the development of Ag-based therapies, such as Ag-specific DNA vaccination or infusion of Ag-coupled cells.

PMID: 28257655 [PubMed – in process]

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Subcutaneous immunoglobulins for the treatment of a patient with antisynthetase syndrome and secondary chronic immunodeficiency after anti-CD20 treatment: a case report.

J Med Case Rep. 2017 Mar 04;11(1):58

Authors: Cherin P, de Jaeger C, Crave JC, Delain JC, Tadmouri A, Amoura Z

Abstract
BACKGROUND: Antisynthetase syndrome is a rare and debilitating multiorgan disease characterized by inflammatory myopathy, interstitial lung disease, cutaneous involvement, and frequent chronic inflammation of the joints. Standard treatments include corticosteroids and immunosuppressants. In some cases, treatment resistance may develop. Administration of immunoglobulins intravenously is recommended in patients with drug-resistant antisynthetase syndrome.
CASE PRESENTATION: Here, we describe the case of a 56-year-old woman of Algerian origin. She is the first case of a patient with multidrug-resistant antisynthetase syndrome featuring pulmonary involvement and arthropathy, and chronic secondary immune deficiency with recurrent infections, after anti-CD20 treatment, in which her primary antisynthetase syndrome-related symptoms and secondary immune deficiency were treated successfully with subcutaneous administration of immunoglobulin. The administration of immunoglobulin subcutaneously was introduced at a dose of 2 g/kg per month and was well tolerated. Clinical improvement was observed within 3 months of initiation of subcutaneous administration of immunoglobulin. After 22 months of treatment, she showed a significant improvement in terms of muscle strength, pulmonary involvement, arthralgia, and immunodeficiency. Her serum creatine phosphokinase and C-reactive protein levels remained normal. Finally, she was compliant and entirely satisfied with the treatment.
CONCLUSIONS: Taken together, these observations suggest that administration of immunoglobulin subcutaneously may be a useful therapeutic approach to tackle steroid-refractory antisynthetase syndrome while ensuring minimal side effects and improved treatment compliance. This treatment also allowed, in our case, for the regression of the chronic immunodeficiency secondary to rituximab treatment.

PMID: 28257650 [PubMed – in process]

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Clinical Features and Genetic Analysis of 48 Patients with Chronic Granulomatous Disease in a Single Center Study from Shanghai, China (2005-2015): New Studies and a Literature Review.

J Immunol Res. 2017;2017:8745254

Authors: Wu J, Wang WF, Zhang YD, Chen TX

Abstract
Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, which is characterized by recurrent infections due to defective phagocyte NADPH oxidase enzyme. Nowadays, little is known about Chinese CGD patients. Here we report 48 CGD patients in our single center study, which is the largest cohort study from Mainland China. The ratio of male to female was 11 : 1. The mean onset age was 0.29 years old, and 52% patients had an onset within the 1st month of life. The mean diagnosis age was 2.24 years old. 11 patients (23%) had died with an average age of 2.91 years old. 13 patients (28%) had positive family histories. The most prevalent infectious sites were the lungs (77%), followed by gastrointestinal tract (54%), lymph nodes (50%), and skin (46%). In addition, septicopyemia, thrush, and hepatosplenomegaly were also commonly observed, accounting for 23%, 23%, and 40% of the cases. Lesions due to BCG vaccination occurred in more than half of the patients. X-linked CGD due to CYBB gene mutations accounted for 75% of the cases, and 11 of them were novel mutations. Autosomal recessive inheritance accounted for 6% patients, including 1 patient with CYBA, 1 with NCF1, and 1 with NCF2 gene mutations.

PMID: 28251166 [PubMed – in process]

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Empyema due to Streptococcus Pneumoniae Serotype 9V in a Child Immunized with 13-Valent Conjugated Pneumococcal Vaccine.

Balkan Med J. 2017 Jan;34(1):74-77

Authors: Sütçü M, Aktürk H, Karagözlü F, Somer A, Gürler N, Salman N

Abstract
BACKGROUND: Clinical vaccine failure is the occurence of the specific vaccine-preventable disease in an appropriately and fully vaccinated person after enough time has elapsed for protection against the antigens of the vaccine to develop. Fully immunized cases with pneumoccal vaccine may sometimes develop a complicated pneumonia with empyema caused by a vaccine serotype.
CASE REPORT: A 2 year-old male patient was admitted with the complaints of fever. On the basis of findings and laboratory results, the patient was diagnosed as having empyema. He was successfully treated with parenteral antibiotics and chest tube drainage. The pleural fluid culture and hemoculture of the patient yielded penicillin-susceptible pneumococci and the isolate was identified as serotype 9V. The patient had been vaccinated with a 13-valent pneumococcal conjugate vaccine according to the Turkish national immunization schedule at 2, 4, 6 and 12 months of age. His medical history and basic immunological profile were inconsistent with a primary immunodeficiency.
CONCLUSION: The failure of the PCV13 vaccine may results in a complicated pneumonia with empyema. It is important to investigate serotypes of pneumococci in these cases to determine other possible vaccine failures due to PCV13 and to study the underlying mechanisms.

PMID: 28251028 [PubMed – in process]

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Achromobacter xylosoxidans Septic Arthritis in a Child with Primary Immunodeficiency.

J Glob Infect Dis. 2017 Jan-Mar;9(1):36-37

Authors: Singh A, Hussain A, Jain R, Aishwarya K, Tak V, Thakur P

PMID: 28250627 [PubMed – in process]

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