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Activated PI3K delta syndrome

GtoPdb Disease Summaries

This section gives an overview of the disease, and where available shows the following:

  • Synonyms: Shows known synonyms for the disease.
  • Description: Gives a basic description/definition of the disease.
  • Database Link: External links to the same disease at the Disease Ontology, OMIM or Orphanet sites.
  • Immunopharmacology comments: General comments about the target's role in immunopharmacology, provided by GtoImmuPdb curators.
  • Associated with: Counts are displayed for the total targets the disease is associated with in GtoPdb. The counts of targets and ligands of immunological relevance associated to the disease are also shown.

More information can be found in the help pages.

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Disease ID:1199
Name:Activated PI3K delta syndrome
Associated with:1 target
1 immuno-relevant target
3 immuno-relevant ligands
Synonyms
APDS/PASLI | Immunodeficiency 14 | p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency
Description
A rare autosomal dominant, genetic disease causing primary immunodeficiency and characterised by lymphadenopathy, immunodeficiency leading to recurrent infections, and an increased risk of EBV-associated lymphoma.
Database Links
OMIM: 615513
Orphanet: ORPHA397596

Targets

GtoPdb Disease Summaries - Targets

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Where available, information is display on the role of the target in the disease; drugs which target the disease and their therapeutic use and side-effects.

If there is mutation data curated in GtoPdb this is indicated, with a link back to the appropriate section on the target detailed view page

Immuno ligand interactions - If available, a table of immuno-relevant ligands is shown. These ligands have been curated as having an association to the disease and possess interaction data with the target in GtoPdb. The approval status of the ligand is shown, along with curator comments and an indication of whether the target is considered the primary target of the ligand.

More information can be found in the help pages.

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Key to terms and symbols
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
Comments:  The effects of constitutive PI3Kδ activation in this syndrome are the opposite (or inverse) of the effects mediated by pharmacological PI3Kδ inhibition.
Mutations:  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta is associated with 2 mutation. Click here for details
Ligand interactions: 
Ligand Comments
nemiralisib
Phase 2 clinical candidate for this condition (see NCT02593539). In the 2nd quarter of 2020, GSK made the decision to terminate the nemiralisib APDS p ...
leniolisib
Phase 1 clinical lead for APDS. Early clinical trial (NCT02435173) results are published. Lymphoproliferation and immune dysregulation are ameliorated ...

Ligands

GtoPdb Disease Summaries - Ligands

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  • Approved: If the ligand is an approved drug this is indicated, along with approval bodies.
  • Immuno: Immuno icon indicates the ligand is immuno-relevant

Click the arrow in the final column to expand comments

  • Immuno Disease Comments: Curatorial comments specifically added as part of GtoImmuPdb. They give more information on the association between the ligand and disease in the context of immunopharmacology.
  • Clinical Use: General clinical comments relating to the ligand and may not necessarily be specific to the disease in question. With hyperlink to more details on the ligand summary pages.
  • Bioactivty Comments: Curatorial comments specifically about the compounds biological activity - with hyperlink to more details on the ligand summary pages.

More information can be found in the help pages.

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Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
nemiralisib
Immuno Disease Comments: Phase 2 clinical candidate for this condition (see NCT02593539). In the 2nd quarter of 2020, GSK made the decision to terminate the nemiralisib APDS programme, in a prioritisation review of their development pipeline.
Clinical Use: Nemiralisib (as GSK2269557) is in Phase 2 clinical development. Two separate studies are underway in patients with chronic obstructive pulmonary disease (COPD; NCT02522299) or the rare genetic condition activated PI3K-delta syndrome (APDS/PASLI; NCT02593539). | View clinical data
Bioactivity Comments: Nemiralisib (GSK2269557) inhibits IFNγ production in vitro and protects against eosinophil recruitment in a relevant brown Norway rat acute OVA model of Th2 driven lung inflammation. The compund is reported to be >1000-fold selective for PI3Kδ over all of the kinases (>250) in the Millipore kinase panel and has low/acceptable hERG liability. | View biological activity
leniolisib 10
Immuno Disease Comments: Phase 1 clinical lead for APDS. Early clinical trial (NCT02435173) results are published. Lymphoproliferation and immune dysregulation are ameliorated in APDS patients following 12 weeks of leniolisib treatment.
Clinical Use: Leniolisib (CDZ173) was evaluated in clinical trial in patients with genetically activated PI3Kδ (i.e. patients with APDS/PASLI; see Phase 2/3 trial NCT02435173). Positive results from NCT02435173 are reported by Rao et al. (2017) [10], showing that leniolisib was well tolerated and improved laboratory and clinical parameters in APDS patients. The FDA approved leniolisib as a treatment for APDS in March 2023 [2]. | View clinical data
Bioactivity Comments: Data are presented for Example 67 in patent WO2012004299 [1]. | View biological activity
sirolimus
Immuno Disease Comments: Phase 1/2 clinical candidate for APDS (NCT03383380).
Clinical Use: Sirolimus is used for prophylaxis of renal transplant rejection [4,11], and may be used in combination with . In June 2015 the US FDA approved sirolimus for the treatment of lymphangioleiomyomatosis, a rare proliferative but benign lung disease [9].
Nab-sirolimus (ABI-009; Fyarro®) is an albumin-bound nanoparticle formulation of sirolimus that was developed by Aadi Bioscience as the first treatment for advanced malignant perivascular epithelioid cell neoplasms (PEComa; see NCT02494570) [6,12]. Fyarro® was approved by the FDA in November 2021.
In May 2023 the EMA expanded authorisation to include the treatrment of angiofibroma of tuberous sclerosis. | View clinical data
Bioactivity Comments: In vitro studies have been performed and these show that sirolimus inhibits MERS-CoV infection of Huh7 cells [3,5]. This mechanism could also be applied to SAR-CoV-2 infection. | View biological activity

References

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1. Cooke NG, Fernandes GDSP, Graveleau N, Hebach C, Hogenauer K, Hollingworth G, Smith AB, Soldermann N, Stowasser F, Strang R et al.. (2012) Tetrahydro-pyrido-pyrimidine derivatives. Patent number: WO2012004299. Assignee: Novartis Ag. Priority date: 06/07/2010. Publication date: 12/01/2012.

2. Duggan S, Al-Salama ZT. (2023) Leniolisib: First Approval. Drugs, 83 (10): 943-948. [PMID:37256490]

3. Dyall J, Gross R, Kindrachuk J, Johnson RF, Olinger Jr GG, Hensley LE, Frieman MB, Jahrling PB. (2017) Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs, 77 (18): 1935-1966. [PMID:29143192]

4. Kelly PA, Gruber SA, Behbod F, Kahan BD. (1997) Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy, 17 (6): 1148-56. [PMID:9399599]

5. Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, Traynor D, Johnson RF, Dyall J, Kuhn JH et al.. (2015) Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob Agents Chemother, 59 (2): 1088-99. [PMID:25487801]

6. Kopparthy P, Murphy M. (2021) Rapid and Durable Response With Nab-Sirolimus After Everolimus Failure in a Patient With Perivascular Epithelioid Cell Tumors (PEComas) of the Uterus. Cureus, 13 (5): e14951. DOI: 10.7759/cureus.14951 [PMID:34123648]

7. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M et al.. (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol, 15 (1): 88-97. [PMID:24165795]

8. Luo Y, Xia Y, Wang W, Li Z, Jin Y, Gong Y, He T, Li Q, Li C, Yang J. (2018) Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome. Clin Immunol, 197: 60-67. [PMID:30138677]

9. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM et al.. (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med, 364 (17): 1595-606. [PMID:21410393]

10. Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M et al.. (2017) Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood, 130 (21): 2307-2316. [PMID:28972011]

11. Vasquez EM. (2000) Sirolimus: a new agent for prevention of renal allograft rejection. Am J Health Syst Pharm, 57 (5): 437-48; quiz 449-51. [PMID:10711524]

12. Wagner AJ, Ravi V, Riedel RF, Ganjoo K, Van Tine BA, Chugh R, Cranmer L, Gordon EM, Hornick JL, Du H et al.. (2021) nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors. J Clin Oncol, 39 (33): 3660-3670. [PMID:34637337]