How ERDITI Functions as a Public–Private Partnership

<p>The working procedure guarantees continuity all the way from research to development of a drug. After the ERDITI scientific advisory board's assessment of the request, industry partners are questioned about the availability of molecules belonging to the pharmacological classes of interest. Several molecules may be of strategic interest for the industry partner, and sponsored research should be negotiated directly outside the framework of this working procedure. If there are no molecules available, the process ends. If molecules are available, a specific agreement is signed and the industry partner provides molecules required for preclinical studies. If promising results arise from preclinical studies, the lead academic partner asks the industry partner whether it wishes to exercise the option to further develop the drug. The industry partner may decide to exploit the results and develop one of the molecules through a worldwide exclusive license. Alternatively, the industry partner may decide not to exploit the results and grant necessary license rights to a third party for the development of the molecule for treating the rare disease.</p

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Objective<p>Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS.</p>Results<p>The proportion of CD25^highCD127^low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3⁺CD4⁺ T cells from ALPS patients and thus an abnormally low proportion of CD25^highFOXP3⁺ Helios⁺ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3^lowCD45RA⁺) and an unusual subpopulation (CD4⁺CD127^lowCD15s⁺CD45RA⁺). Despite this abnormal phenotype, the CD25^highCD127^low Tregs’ suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression.</p>Conclusion<p>An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.</p

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Objective<p>Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS.</p>Results<p>The proportion of CD25^highCD127^low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3⁺CD4⁺ T cells from ALPS patients and thus an abnormally low proportion of CD25^highFOXP3⁺ Helios⁺ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3^lowCD45RA⁺) and an unusual subpopulation (CD4⁺CD127^lowCD15s⁺CD45RA⁺). Despite this abnormal phenotype, the CD25^highCD127^low Tregs’ suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression.</p>Conclusion<p>An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.</p

Inherited MST1 Deficiency Underlies Susceptibility to EV-HPV Infections

<div><p>Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare <em>ERCC3</em> variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.</p> </div

Mean values for random CIS formation (1000 IS) determined either with computer simulations or mathematically.

<p>Simulations were performed with 50000 runs each. g, haploid size of the human genome: 3.12 x 10⁶kb; <i>d</i>_n, genomic window size [kb] for CIS of n^th order: <i>d</i>₂ = 30, <i>d</i>₃ = 50, and <i>d</i>₄ = 100; <i>n</i>_is, number of (assumed) sampled integration sites: 1000.</p

Immunophenotyping of the patient.

A<p>Normal ranges were obtained from internal laboratory controls (N = 10) unless specified otherwise.</p>B<p>normal ranges from the work of Lugada <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Lugada1" target="_blank">[47]</a>.</p>C<p>normal ranges taken from the work of Nehme <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Nehme1" target="_blank">[30]</a>.</p>D<p>normal ranges taken from the work of Shearer <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Shearer1" target="_blank">[48]</a>.</p>E<p>normal ranges taken from the work of Bisset <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Bisset1" target="_blank">[49]</a>.</p>F<p>normal ranges taken from the work of Eidenscheck <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Eidenschenk1" target="_blank">[50]</a>.</p

Homozygous <i>MST1</i> nonsense mutation in one patient with EV-HPV, bacterial and fungal infections.

<p>(A) Pedigree of the family with EV-HPV, bacterial and fungal infections. Generations are designated by a Roman numeral (I, II). P1 is represented by a black symbol. The symbol *indicates the individuals genotyped with the Affymetrix Genome-wide SNP 6.0 array. The Familial segregation of the mutation R115X is shown on the pedigree. (B) Automated sequencing profile, showing the R115X <i>MST1</i> mutation in gDNA extracted from EBV-B cells from the patient and comparison with the sequence obtained from a healthy control. The C→T mutation leads to the replacement at residue 115 of an Arg (R) residue by a STOP codon (X). (C) Schematic representation of the structure of the MST1 protein adapted from the work of Nehme <i>et al. </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Nehme1" target="_blank">[30]</a>. R115X is situated in the kinase domain, close to the previously reported R117X mutation described by Nehme <i>et al.,</i> indicated by a black arrow. The second mutation (1103delT X369) described by Nehme <i>et al.,</i> 1103delT X369, and the mutation described by Abdollahpour <i>et al.</i> (W250X) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044010#pone.0044010-Abdollahpour1" target="_blank">[31]</a> are also indicated by black arrows.</p

T-cell proliferation in response to mitogens and antigens, as assessed by thymidine incorporation^A.

A<p>3H-TdR incorporation in cpm/10³.</p>B<p>normal ranges from internal laboratory controls.</p

Whole-exome analysis of P1^a.

<p>Coding variants include missense, nonsense, frameshift, in-frame deletions and insertions and readthrough variants.</p><p>Essential splice variants include all variants found in the first two base pairs or the last two base pairs of introns.</p>a<p>Both homozygous and heterozygous variations are included.</p

Formulas based statistical analysis of the results on CIS formation in clinical samples derived from 2 clinical X-SCID gene therapy studies [unpublished data].

<p>Calculations were performed on the haploid size of the human genome (3.12 × 10⁶ kb) and on the basis of an IS skewing (25% of all IS) to the +/− 5 kb TSS region, for which an (*) uniform or a (^§) triangular IS distribution, respectively, was assumed. 75% of IS were assumed to be uniformly distributed over the remaining human genome. The genomic window size chosen for CIS of 2^nd order was 30 kb. CIS, number of identified CIS of 2^nd order in patient and control samples pre- and post-transplant; IS, number of all unique identified integration sites in patient and control samples pre- and post-transplant; MV, mean value.</p