Congenital amegakaryocytic thrombocytopenia (CAMT) is life-threatening and extremely rare genetic disorder caused by the absence or severe reduction of megakaryocytes (platelet-producing cells) in the bone marrow. This condition results in profound thrombocytopenia beginning early in life. If untreated, CAMT culminates in bone marrow failure (BMF) along with an increasing risk of life-threatening hemorrhage or leukemia. The prevalence of CAMT has not been characterized, with fewer than 100 cases documented in the literature.
Fig. 1 Mutations in the MPL gene cause congenital amegakaryocytic thrombocytopenia (CAMT). (Pecci, Alessandro, et al., 2018)
The pathogenesis of congenital amegakaryocytic thrombocytopenia (CAMT) is primarily linked to genetic mutations affecting the thrombopoietin (TPO) signaling pathway. Here is an overview of the pathogenesis of CAMT:
MPL Gene Mutation
The dominant cause of CAMT appears with alterations within the MPL gene which is responsible for encoding the receptor of thrombopoietin. Thrombopoietin is an essential hormone responsible for controlling platelet production by promoting the development and maturation of megakaryocytes in the bone marrow.
Impaired Megakaryopoiesis
Defective signaling of the thrombopoietin receptor due to mutations of MPL gene results in aberrant megakaryopoiesis. Megakaryocytes, the precursor cells that form platelets, do not properly mature within the bone marrow.
Reduced Platelet Production
The lack or decrease of active megakaryocytes in the bone marrow leads to a reduction in the formation of blood platelets. This causes the patient to develop thrombocytopenia, or a state wherein the patient has a lower count of platelets in blood.
| Therapy | Types | Targets | Mechanism of Action | Development Stage |
|---|---|---|---|---|
| Eltrombopag | Small molecule (TPO mimetic) | MPL receptor | Activate residual MPL signaling in Type II CAMT | Approved |
| Lenti-MPL Gene Therapy | Gene therapy | MPL gene in HSCs | Restore functional MPL expression in hematopoietic stem cells (HSCs) | Phase I/II |
| Jak2/STAT5 Activators | Small molecule | Jak2/STAT5 pathway | Bypass defective TPO/MPL signaling to stimulate megakaryopoiesis | Research stage |
| HSCT with Gene-Corrected HSCs | Cell therapy and gene editing | Patient-derived HSCs | Autologous transplant after MPL correction | Early clinical trials |
| Antisense Oligonucleotides (ASOs) | RNA therapy | MPL mRNA | Suppress aberrant splicing or nonsense mutations | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
At Protheragen, we are committed to advancing the fight against myeloproliferative disorders, including congenital amegakaryocytic thrombocytopenia (CAMT), by offering comprehensive diagnostic and therapeutic development services. Our expertise spans the entire spectrum of disease management, from in vitro diagnostic (IVD) kit development to innovative therapeutics development. Leveraging cutting-edge technologies and deep scientific knowledge, we specialize in creating highly accurate disease models that replicate the complexities of CAMT.
At Protheragen, we offer comprehensive pharmacodynamic (PD), pharmacokinetic (PK), and toxicology research services to support the development and regulatory approval of potential therapies for congenital amegakaryocytic thrombocytopenia (CAMT). If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
Myeloproliferative Disorders (MPDs)
Bone Marrow Failure Syndromes (BMFS)
