CXCR4 in Primary Immunodeficiency Diseases
Primary immunodeficiency (PI) diseases are a group of hereditary, chronic disorders in which part of the body’s immune system is missing or functions improperly, leaving patients highly susceptible to infection and other complications. PI diseases have different etiologies; some are primarily associated with a single aspect of immune system, while others are related to multiple components. Aberrant functioning of CXCR4 is one of the mechanisms that is associated with certain PI diseases.
A specific PI disease called WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is caused by mutations in the CXCR4 receptor gene, leading to abberant trafficking of specific immune cells that are critical for proper immune system functions. As a result, patients have increased rates of severe health complications, including infections such as pneumonias, cellulitis, meningitis, deep soft tissue abscesses, and skin infections. Infections begin in early childhood and recur throughout life. Patients with WHIM also characteristically have numerous warts on hands, feet, trunk and various mucosal surfaces that in some cases progress to cancer. WHIM syndrome is a disease of considerable morbidity, with no currently available therapy to address the underlying mechanism of disease. Given the targeting of CXCR4 by our drug candidate, X4P-001-RD, we believe it may offer disease modifying benefits for WHIM patients.
Therapeutic targeting of CXCR4 in WHIM syndrome
Within the bone marrow, a normal CXCR4 receptor regulates the release of neutrophils and leukocytes into the blood stream to ensure normal immune surveillance functions throughout the body. In patients with WHIM syndrome, mutations to the CXCR4 receptor cause aberrant signaling leading to prolonged retention of neutrophils and leukocytes in the bone marrow and inadequate immune function.
By blocking the binding of CXCL12 ligand to the CXCR4 receptor, our therapeutics are designed to normalize the signaling from the mutant CXCR4 receptor. As a result, our therapeutics may promote normal release of neutrophils and leukocytes and restore normal immune surveillance.
The Jeffrey Modell Foundation (JMF), a non-profit organization for primary immunodeficiency diseases, and X4 Pharmaceuticals co-sponsored a genetic screening study to help identify patients who have WHIM syndrome, at no cost to patients or insurance.
CXCR4 genetic testing is also available at cost through other commercial or research laboratories.
Selected scientific references
- Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genetics 2003;34(1):70-74.
- Gulino AV, Moratto D, Sozzani S, et al. Altered leukocyte response to CXCL12 in patients with Warts Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome. Blood 2004;104(2):444-452.
- Kawai T and Malech, HL. WHIM Syndrome: Congenital Immune Deficiency Disease. Curr Opin Hematol. 2009; 16(1): 20–26.
- Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood 2011;118(18):4963-4966.
- McDermott DH, Liu Q, Ulrick J, Kwatemaa N, Anaya-O’Brien S, Penzak SR, Filho JO, Priel DA, Kelly C, Garofalo M, Littel P, Marquesen MM, Hilligoss D, Decastro R, Fleisher TA, Kuhns DB, Malech HL, Murphy PM. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood. 2011 Nov 3;118(18):4957-62. doi: 10.1182/blood-2011-07-368084.
- McDermott DH, Liu Q, Velez D, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr 10;123(15):2308-16.