What is Paroxysmal Nocturnal Hemoglobinuria?

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells. The classic clinical triad of PNH includes:

● Hemolytic Anemia: Characterized primarily by chronic intravascular hemolysis, often manifesting as dark, cola-colored urine (hemoglobinuria) upon waking.

● Bone Marrow Failure: Some patients present with concurrent aplastic anemia (AA) or myelodysplastic syndromes (MDS).

● Thrombosis: High incidence of venous thrombosis, potentially affecting critical sites such as hepatic, mesenteric, and cerebral veins, representing a leading cause of mortality in PNH patients.

PNH patients most commonly succumb to thrombosis or progressive cytopenia. The estimated incidence is 1 to 5 cases per million individuals.
 

Pathogenesis
 

The pathological defect in PNH originates from mutations in the PIG-A gene, located on the X chromosome (Xp22.1). This gene encodes a subunit of the enzyme phosphatidylinositol glycan class A (PIG-A), which is essential for the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. The GPI anchor is required for the membrane attachment of a group of proteins on blood cells, including complement decay-accelerating factor (CD55) and the membrane attack complex inhibitory protein CD59. The absence of these proteins renders PNH erythrocytes highly susceptible to intravascular hemolysis, leading to clinical manifestations such as hemolysis and thrombosis. Over a hundred different PIG-A gene mutations have been reported, most being single-nucleotide changes, with longer insertions or deletions being rarer and no clear mutational hotspot region identified.

(Image: PubMed)

The presence of a PIG-A mutation alone is insufficient to drive clonal expansion. The pathogenesis of PNH also involves immune evasion, clonal selection, and secondary genetic mutations. PNH clonal cells, lacking GPI-anchored proteins, can evade attack by the immune system, thereby gaining a survival and growth advantage. Furthermore, the expansion of the PNH clone is associated with immune selection pressure within the bone marrow microenvironment, possibly stemming from underlying bone marrow failure or other myeloproliferative disorders. Additional genetic mutations, such as in JAK2or CALR, may occur within the PNH clone, further promoting clonal expansion and disease progression.

(Image: PubMed)

 

Gene Therapy
 

● PIG-A Gene Replacement Therapy: Utilizes lentiviral vectors to deliver a functional PIG-A gene into patient hematopoietic stem cells, restoring GPI-anchored protein expression. Moreau-Gaudry et al. successfully demonstrated PIG-A gene transduction in mouse models and expanded the corrected stem cells using a drug-selection system.

● Complement System-Targeted Gene Therapy: An AAV vector-based gene therapy (HMI-104) delivers a gene encoding a C5 antibody for expression in the liver, inhibiting complement activation. In animal experiments, this approach completely inhibited in vitro hemolysis.

Mouse Models

● PIG-A Conditional Knockout Mice: Utilize systems like Vav-Cre or Mx1-Cre to achieve hematopoietic-specific knockout of the PIG-A gene, modeling the GPI deficiency phenotype observed in human PNH. These mice exhibit GPI-deficient hematopoietic cells, mild hemolysis, and a propensity for bone marrow failure.

MingCeler Biotech Facilitates Gene Therapy

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various PNH mouse models according to client needs, such as PIG-A conditional knockout mice. We welcome inquiries!

 

References:

[1] Li Liyan, Fu Rong. Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria. Chinese Journal of Hematology, 2018, 39(6): 527-528. DOI: 10.3760/cma.j.issn.0253-2727.2018.06.022

[2] Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017 May 18;3:17028. doi: 10.1038/nrdp.2017.28. PMID: 28516949; PMCID: PMC7879566.

[3] Luzzatto L, Nakao S. Pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood. 2025 Jun 26;145(26):3077-3088. doi: 10.1182/blood.2024025975. PMID: 40089995.

[4] Perry C, Von Buttlar X, Thota S. The Advancing Landscape of Paroxysmal Nocturnal Hemoglobinuria Treatment. Turk J Haematol. 2025 May 22;42(2):74-81. doi: 10.4274/tjh.galenos.2025.2025.0054. Epub 2025 Apr 21. PMID: 40257298; PMCID: PMC12099479.

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