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Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.

October 30, 2020 By Manish Butte

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.

J Immunol. 2020 Oct 28;:

Authors: Diaz N, Juarez M, Cancrini C, Heeg M, Soler-Palacín P, Payne A, Johnston GI, Helmer E, Cain D, Mann J, Yuill D, Conti F, Di Cesare S, Ehl S, Garcia-Prat M, Maccari ME, Martín-Nalda A, Martínez-Gallo M, Moshous D, Santilli V, Semeraro M, Simonetti A, Suarez F, Cavazzana M, Kracker S

Abstract
Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for ≤96 wk.

PMID: 33115853 [PubMed – as supplied by publisher]

Evaluation of patients with primary immunodeficiency associated with Bacille Calmette-Guerin (BCG)-vaccine-derived complications.

October 30, 2020 By Manish Butte

Evaluation of patients with primary immunodeficiency associated with Bacille Calmette-Guerin (BCG)-vaccine-derived complications.

Allergol Immunopathol (Madr). 2020 Oct 25;:

Authors: Sohani M, Habibi S, Delavari S, Shahkarami S, Yazdani R, Shirmast P, Nazari F, Shad TM, Mamishi S, Azizi G, Anka AU, Hassanpour G, Kalantari A, Shariat M, Shafiei A, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination has a great impact on the prevention of severe complications of tuberculosis. However, in patients with primary immunodeficiencies (PID), it can lead to severe complications such as severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial disease. This study highlights the demographics, clinical complications and laboratory parameters among PID patients associated with BCG vaccination side effects.
METHODS: One hundred and thirty-seven PID patients with BCGosis were evaluated in this study, based on the complications following BCG vaccination.
RESULTS: The mean age of the patients with BCG complications at the time of the first visit was five years. The within-group comparison of patients showed a highly significant incidence of pneumonia and hepatomegaly in severe combined immunodeficiency patients. Furthermore, the immunologic data showed an increase in the overall rates of lymphocytes such as CD3+, CD4+ and CD8 + T cells in Mendelian susceptibility to mycobacterial disease patients. The level of immunoglobulins has also increased in chronic granulomatous disease patients.
CONCLUSION: The high rate of undiagnosed PIDs predisposes individuals to a high risk of severe side effects as a result of BCG vaccination, as well as infants that are less than one month of age. Therefore, there is a need for early screening and diagnosis of PIDs before exposing unknown PID status patients to BCG vaccination. The benefits of screening and early diagnosis of PID cannot be overemphasized, especially in patients with a previous family history of immunodeficiency.

PMID: 33115608 [PubMed – as supplied by publisher]

The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2.

October 30, 2020 By Manish Butte

The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2.

Sci Rep. 2019 09 24;9(1):13758

Authors: Vakkilainen S, Skoog T, Einarsdottir E, Middleton A, Pekkinen M, Öhman T, Katayama S, Krjutškov K, Kovanen PE, Varjosalo M, Lindqvist A, Kere J, Mäkitie O

Abstract
RMRP was the first non-coding nuclear RNA gene implicated in a disease. Its mutations cause cartilage-hair hypoplasia (CHH), an autosomal recessive skeletal dysplasia with growth failure, immunodeficiency, and a high risk for malignancies. This study aimed to gain further insight into the role of RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) in cellular physiology and disease pathogenesis. We combined transcriptome analysis with single-cell analysis using fibroblasts from CHH patients and healthy controls. To directly assess cell cycle progression, we followed CHH fibroblasts by pulse-labeling and time-lapse microscopy. Transcriptome analysis identified 35 significantly upregulated and 130 downregulated genes in CHH fibroblasts. The downregulated genes were significantly connected to the cell cycle. Multiple other pathways, involving regulation of apoptosis, bone and cartilage formation, and lymphocyte function, were also affected, as well as PI3K-Akt signaling. Cell-cycle studies indicated that the CHH cells were delayed specifically in the passage from G2 phase to mitosis. Our findings expand the mechanistic understanding of CHH, indicate possible pathways for therapeutic intervention and add to the limited understanding of the functions of RMRP.

PMID: 31551465 [PubMed – indexed for MEDLINE]

Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.

October 29, 2020 By Manish Butte

Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.

J Clin Immunol. 2020 Oct 27;:

Authors: NaserEddin A, Dinur-Schejter Y, Shadur B, Zaidman I, Even-Or E, Averbuch D, Shamriz O, Tal Y, Shaag A, Warnatz K, Elpeleg O, Stepensky P

Abstract
PURPOSE: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients.
METHODS: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019.
RESULTS: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective.
CONCLUSION: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.

PMID: 33111199 [PubMed – as supplied by publisher]

Treating primary immunodeficiencies with defects in NK cells: from stem cell therapy to gene editing.

October 29, 2020 By Manish Butte

Treating primary immunodeficiencies with defects in NK cells: from stem cell therapy to gene editing.

Stem Cell Res Ther. 2020 Oct 27;11(1):453

Authors: Eguizabal C, Herrera L, Inglés-Ferrándiz M, Izpisua Belmonte JC

Abstract
Primary immunodeficiency diseases (PIDs) are rare diseases that are characterized by genetic mutations that damage immunological function, defense, or both. Some of these rare diseases are caused by aberrations in the normal development of natural killer cells (NKs) or affect their lytic synapse. The pathogenesis of these types of diseases as well as the processes underlying target recognition by human NK cells is not well understood. Utilizing induced pluripotent stem cells (iPSCs) will aid in the study of human disorders, especially in the PIDs with defects in NK cells for PID disease modeling. This, together with genome editing technology, makes it possible for us to facilitate the discovery of future therapeutics and/or cell therapy treatments for these patients, because, to date, the only curative treatment available in the most severe cases is hematopoietic stem cell transplantation (HSCT). Recent progress in gene editing technology using CRISPR/Cas9 has significantly increased our capability to precisely modify target sites in the human genome. Among the many tools available for us to study human PIDs, disease- and patient-specific iPSCs together with gene editing offer unique and exceptional methodologies to gain deeper and more thorough understanding of these diseases as well as develop possible alternative treatment strategies. In this review, we will discuss some immunodeficiency disorders affecting NK cell function, such as classical NK deficiencies (CNKD), functional NK deficiencies (FNKD), and PIDs with involving NK cells as well as strategies to model and correct these diseases for further study and possible avenues for future therapies.

PMID: 33109263 [PubMed – in process]

WAS Promoter-Driven Lentiviral Vectors Mimic Closely the Lopsided WASP Expression during Megakaryocytic Differentiation.

October 27, 2020 By Manish Butte

WAS Promoter-Driven Lentiviral Vectors Mimic Closely the Lopsided WASP Expression during Megakaryocytic Differentiation.

Mol Ther Methods Clin Dev. 2020 Dec 11;19:220-235

Authors: Muñoz P, Tristán-Manzano M, Sánchez-Gilabert A, Santilli G, Galy A, Thrasher AJ, Martin F

Abstract
Transplant of gene-modified autologous hematopoietic progenitors cells has emerged as a new therapeutic approach for Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency with microthrombocytopenia and abnormal lymphoid and myeloid functions. Despite the clinical benefits obtained in ongoing clinical trials, platelet restoration is suboptimal. The incomplete restoration of platelets in these patients can be explained either by a low number of corrected cells or by insufficient or inadequate WASP expression during megakaryocyte differentiation and/or in platelets. We therefore used in vitro models to study the endogenous WASP expression pattern during megakaryocytic differentiation and compared it with the expression profiles achieved by different therapeutic lentiviral vectors (LVs) driving WAS cDNA through different regions of the WAS promoter. Our data showed that all WAS promoter-driven LVs mimic very closely the endogenous WAS expression kinetic during megakaryocytic differentiation. However, LVs harboring the full-length (1.6-kb) WAS-proximal promoter (WW1.6) or a combination of the WAS alternative and proximal promoters (named AW) had the best behavior. Finally, all WAS-driven LVs restored the WAS knockout (WASKO) mice phenotype and functional defects of hematopoietic stem and progenitor cells (HSPCs) from a WAS patient with similar efficiency. In summary, our data back up the use of WW1.6 and AW LVs as physiological gene transfer tools for WAS therapy.

PMID: 33102615 [PubMed]

Interleukin-1 Receptor-Associated Kinase 4 Deficiency in a Greek Teenager.

October 27, 2020 By Manish Butte

Interleukin-1 Receptor-Associated Kinase 4 Deficiency in a Greek Teenager.

Case Reports Immunol. 2020;2020:8846827

Authors: Karananou P, Alataki A, Papadopoulou-Alataki E

Abstract
Background: Human interleukin- (IL-) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently described primary immunodeficiency. It is a rare, autosomal recessive immunodeficiency that impairs toll/IL-1R immunity, except for the toll-like receptor (TLR) 3- and TLR4-interferon alpha (IFNA)/beta (IFNB) pathways. Case Report. We report the first patient in Greece with IRAK-4 deficiency. From the age of 8 months, she presented with recurrent infections of the upper and lower respiratory tract and skin abscesses. For this, she had been repeatedly hospitalized and treated empirically with intravenous antibiotics. No severe viral, mycobacterial, or fungal infections were noted. Her immunological laboratory evaluation revealed low serum IgA and restored in subsequent measurements; normal IgG, IgM, and IgE; and normal serum IgG subclasses. Peripheral blood immunophenotyping by flow cytometry and dihydrorhodamine (DHR) test revealed normal counts. She was able to make functional antibodies against vaccine antigens, including tetanus and diphtheria. She was administered with empirical IgG substitution for 5 years until the age of 12 years, and she has never experienced invasive bacterial infections so far. DNA analysis revealed a heterozygous variant in the patient: c.823delT (p.S275fs ∗ 13 at protein level) in the IRAK4 gene.
Conclusions: The importance of clinical suspicion is emphasized in order to confirm the diagnosis by IRAK4 gene sequencing and provide the appropriate treatment for this rare primary immunodeficiency, as soon as possible.

PMID: 33101742 [PubMed]

Real-life gait assessment in degenerative cerebellar ataxia: Toward ecologically valid biomarkers.

October 27, 2020 By Manish Butte

Real-life gait assessment in degenerative cerebellar ataxia: Toward ecologically valid biomarkers.

Neurology. 2020 09 01;95(9):e1199-e1210

Authors: Ilg W, Seemann J, Giese M, Traschütz A, Schöls L, Timmann D, Synofzik M

Abstract
OBJECTIVES: With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid motor biomarkers are highly warranted. In this observational study, we aimed to unravel and validate markers of ataxic gait in real life by using wearable sensors.
METHODS: We assessed gait characteristics of 43 patients with degenerative cerebellar disease (Scale for the Assessment and Rating of Ataxia [SARA] 9.4 ± 3.9) compared with 35 controls by 3 body-worn inertial sensors in 3 conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n = 21). Movement analysis focused on measures of spatiotemporal step variability and movement smoothness.
RESULTS: A set of gait variability measures was identified that allowed us to consistently identify ataxic gait changes in all 3 conditions. Lateral step deviation and a compound measure of spatial step variability categorized patients vs controls with a discrimination accuracy of 0.86 in real life. Both were highly correlated with clinical ataxia severity (effect size ρ = 0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the clinical SARAposture&gait subscore, with highest effect sizes for real-life walking (d = 0.67).
CONCLUSIONS: We identified measures of ataxic gait that allowed us not only to capture the gait variability inherent in ataxic gait in real life, but also to demonstrate high sensitivity to small differences in disease severity, with the highest effect sizes in real-life walking. They thus represent promising candidates for motor markers for natural history and treatment trials in ecologically valid contexts.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a set of gait variability measures, even if accessed in real life, correlated with the clinical severity of ataxia in patients with degenerative cerebellar disease.

PMID: 32611635 [PubMed – indexed for MEDLINE]

Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand.

October 26, 2020 By Manish Butte

Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand.

J Paediatr Child Health. 2020 Oct;56(10):1508-1513

Authors: Richards S, Gennery AR, Davies EG, Wong M, Shaw PJ, Peake J, Fraser C, Gray P, Brothers S, Sinclair J, Prestidge T, Preece K, Quinn P, Ramachandran S, Loh R, McLean-Tooke A, Mitchell R, Cole T, Australasian Society of Clinical Immunology and Allergy (ASCIA) Transplantation and Immunodeficiency (TAPID) group

Abstract
This consensus document outlines the recommendations from the Australasian Society of Clinical Immunology and Allergy Transplantation and Primary Immunodeficiency group for the diagnosis and management of patients with severe combined immunodeficiency. It also provides a proposed framework for the early investigation, management and supportive care prior to haematopoietic stem cell transplantation.

PMID: 33099818 [PubMed – in process]

Folliculotropic mycosis fungoides driven by DOCK8 immunodeficiency syndrome.

October 26, 2020 By Manish Butte

Folliculotropic mycosis fungoides driven by DOCK8 immunodeficiency syndrome.

Pediatr Dermatol. 2020 Oct 25;:

Authors: Rubio-Gonzalez B, Frieden IJ, McCalmont TH, Dorsey M, Funk T, Pincus LB

Abstract
DOCK8 immunodeficiency syndrome (DIDS) represents a rare primary immunodeficiency associated with cutaneous viral infections, allergy, and increased risk of malignancy. We report a case of folliculotropic mycosis fungoides with spontaneous resolution occurring in a patient with DIDS.

PMID: 33099799 [PubMed – as supplied by publisher]