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Results of a Phase 2 Trial of an Oral CXCR4 Antagonist Mavorixafor for Treatment of WHIM Syndrome.

September 2, 2020 By Manish Butte

Results of a Phase 2 Trial of an Oral CXCR4 Antagonist Mavorixafor for Treatment of WHIM Syndrome.

Blood. 2020 Aug 31;:

Authors: Dale DC, Firkin FC, Bolyard AA, Kelley M, Makaryan V, Gorelick KJ, Ebrahim T, Garg V, Tang W, Jiang H, Skerlj R, Beaussant Cohen SL

Abstract
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of mavorixafor from a phase 2, open-label, dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral, small molecule, selective antagonist of the CXCR4 receptor, that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor up to 400 mg QD. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow up of 16.5 months, we observed dose-dependent increases of absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC). At doses at or above 300 mg per day, ANC was maintained above 500 cells/μL for a median of 12.6 hours, and ALC above 1000 cells/μL for up to 16.9 hours. Continued follow-up on the extension study demonstrated a decreased yearly infection rate from 4.63 [95%CI 3.3,6.3] events in the 12 months prior to the trial to 2.27 [95%CI 1.4, 3.5] events for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor 400 mg once-daily mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as # NCT03005327.

PMID: 32870250 [PubMed – as supplied by publisher]

Effect of an awareness campaign on the diagnosis and clinical impact of primary immunodeficiency.

September 2, 2020 By Manish Butte

Effect of an awareness campaign on the diagnosis and clinical impact of primary immunodeficiency.

Med Clin (Barc). 2020 Aug 28;:

Authors: Mateu L, Teniente-Serra A, Rocamora G, Marin-Muñiz A, Pàrraga N, Casas I, Reynaga E, Sopena N, Sabria M, Pedro-Botet ML, los miembros del Comité de Inmunodeficiencias Primarias del Hospital Germans Trias i Pujol

Abstract
BACKGROUND AND OBJECTIVES: Predominantly antibody deficiencies are the most prevalent primary immunodeficiency (PID) in adults. These are rare diseases difficult to diagnose. Therefore, they are diagnosed late. This study aims to evaluate whether an awareness campaign of PIDs among physicians is associated with an increase in number of diagnoses, a reduction in diagnostic delay and diagnosis at earlier stages.
PATIENTS AND METHODS: A single centre, interventional, quasi-experimental study was designed that included 2 periods, period 1 pre-intervention (1986-2008) and period 2 post-intervention (2009-2018). A descriptive comparative study of variables was carried out in both periods.
RESULTS: 116 patients were included [27 (23.3%) in period 1 and 89 (76.7%) in period 2]. The incidence rate increased significantly (0.204 and 1.236/100,000habs./year; P < 0.05), the diagnosis delay tended to be lower (4 vs. 3.73 years). The reasons for diagnostic suspicion were diverse and the burden disease at diagnosis (expressed by bronchiectasis, altered spirometry, ability to generate antibodies by thymus-independent mechanism and need for substitute treatment) tended to decrease in period 2.
CONCLUSIONS: Given the potentially serious complications of patients with late diagnosis of PIDs, it is necessary to create specialized multidisciplinary units, to unify assistance protocols and to design interventions to increase the knowledge of these entities.

PMID: 32868033 [PubMed – as supplied by publisher]

Gene therapy for severe combined immunodeficiencies and beyond.

September 2, 2020 By Manish Butte

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Gene therapy for severe combined immunodeficiencies and beyond.

J Exp Med. 2020 01 06;217(2):

Authors: Fischer A, Hacein-Bey-Abina S

Abstract
Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.

PMID: 31826240 [PubMed – indexed for MEDLINE]

CARD9 Deficiency in a Chinese Man with Cutaneous Mucormycosis, Recurrent Deep Dermatophytosis and a Review of the Literature.

September 1, 2020 By Manish Butte

CARD9 Deficiency in a Chinese Man with Cutaneous Mucormycosis, Recurrent Deep Dermatophytosis and a Review of the Literature.

Mycopathologia. 2020 Aug 31;:

Authors: Wang X, Ding H, Chen Z, Zeng X, Sun J, Chen H, Fu M

Abstract
Deficiency of caspase recruitment domain-containing protein 9 (CARD9) is an autosomal recessive primary immunodeficiency disorder, which typically predisposes immunocompetent individuals to single fungal infections and multiple fungal infections are very rare. We study an otherwise healthy 48-year-old man, who had been admitted to our hospital diagnosed with deep dermatophytosis caused by Trichophyton rubrum for three times at 29, 33 and 48 years old, respectively. At the age of 39 years, he suffered from cutaneous mucormycosis due to Mucor irregularis. Moreover, he had a long history of superficial fungal diseases and occasional oral candidiasis. Whole-exome sequencing revealed two compound heterozygous splicing variants in CARD9 gene, c. 184 + 5 G > T and c. 951G > A, confirmed by Sanger sequencing. Patients with recurrent fungal infections especially invasive fungal infections in the absence of known immunodeficiencies should be tested for CARD9 mutations.

PMID: 32865705 [PubMed – as supplied by publisher]

X-Linked Thrombocytopenia and Vanishing White Matter Disease in a Child: Double Tragedy.

September 1, 2020 By Manish Butte

X-Linked Thrombocytopenia and Vanishing White Matter Disease in a Child: Double Tragedy.

J Clin Immunol. 2020 Aug 31;:

Authors: Pilania RK, Anjani G, Saini AG, Jain R, Suri D, Rawat A

PMID: 32865661 [PubMed – as supplied by publisher]

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.

September 1, 2020 By Manish Butte

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.

J Exp Med. 2020 Nov 02;217(11):

Authors: Helfricht A, Thijssen PE, Rother MB, Shah RG, Du L, Takada S, Rogier M, Moritz J, IJspeert H, Stoepker C, van Ostaijen-Ten Dam MM, Heyer V, Luijsterburg MS, de Groot A, Jak R, Grootaers G, Wang J, Rao P, Vertegaal ACO, van Tol MJD, Pan-Hammarström Q, Reina-San-Martin B, Shah GM, van der Burg M, van der Maarel SM, van Attikum H

Abstract
The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.

PMID: 32865561 [PubMed – as supplied by publisher]

Human NK cell deficiency as a result of biallelic mutations in MCM10.

September 1, 2020 By Manish Butte

Human NK cell deficiency as a result of biallelic mutations in MCM10.

J Clin Invest. 2020 Aug 31;:

Authors: Mace EM, Paust S, Conte MI, Baxley RM, Schmit MM, Patil SL, Guilz NC, Mukherjee M, Pezzi AE, Chmielowiec J, Tatineni S, Chinn IK, Akdemir ZC, Jhangiani SN, Muzny DM, Stray-Pedersen A, Bradley RE, Moody M, Connor PP, Heaps AG, Steward C, Banerjee PP, Gibbs RA, Borowiak M, Lupski JR, Jolles S, Bielinsky AK, Orange JS

Abstract
Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

PMID: 32865517 [PubMed – as supplied by publisher]

Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant.

August 29, 2020 By Manish Butte

Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant.

J Allergy Clin Immunol. 2020 Aug 25;:

Authors: Kutukculer N, Seeholzer T, O’Neill TJ, Graß C, Aykut A, Karaca NE, Durmaz A, Cogulu O, Aksu G, Gehring T, Gewies A, Krappmann D

PMID: 32858082 [PubMed – as supplied by publisher]

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.

August 29, 2020 By Manish Butte

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.

Nat Commun. 2020 07 03;11(1):3355

Authors: Gao L, Emperle M, Guo Y, Grimm SA, Ren W, Adam S, Uryu H, Zhang ZM, Chen D, Yin J, Dukatz M, Anteneh H, Jurkowska RZ, Lu J, Wang Y, Bashtrykov P, Wade PA, Wang GG, Jeltsch A, Song J

Abstract
Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

PMID: 32620778 [PubMed – indexed for MEDLINE]

Plasma C3d levels as a diagnostic marker for complete complement factor I deficiency.

August 28, 2020 By Manish Butte

Plasma C3d levels as a diagnostic marker for complete complement factor I deficiency.

J Allergy Clin Immunol. 2020 Aug 24;:

Authors: Naesens L, Smet J, Tavernier SJ, Schelstraete P, Hoste L, Lambrecht S, Verhelst H, van der Werff Ten Bosch J, Ferster A, Blumental S, Hilbert P, Kerre T, Van de Walle J, Licht C, Roumenina LT, Stordeur P, Haerynck F

PMID: 32853637 [PubMed – as supplied by publisher]