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Activated PI3K delta syndrome

Disease ID:1199
Name:Activated PI3K delta syndrome
Associated with:1 target
1 immuno-relevant target
3 immuno-relevant ligands
APDS/PASLI | Immunodeficiency 14 | p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency
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


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
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 ...
Phase 1 clinical lead for APDS. Early clinical trial (NCT02435173) results are published. Lymphoproliferation and immune dysregulation are ameliorated ...


Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
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
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


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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]