Congenital agranulocytosis is a bone marrow failure disease that is rare and stems primarily from genetic mutations. Given our extensive experience in developing therapies for congenital agranulocytosis, Protheragen is optimally equipped to offer tailored solutions and holistic guidance to help you navigate the complex processes associated with commercializing therapies for congenital agranulocytosis.
Congenital agranulocytosis, or Kostmann syndrome, is a very uncommon genetic condition which affects the body's ability to produce a specific kind of white blood cell-called neutrophils-central to battling bacterial infections. This condition is usually present from birth, causing affected individuals to have repeated and extreme bacterial infections. Estimated to occur in 1 out of 200,000 births, congenital agranulocytosis is frequently diagnosed during infancy due to persistent and harsh infections.
Fig. 1 Effects of monogenic defects in congenital agranulocytosis on myeloid maturation, development, and release from the bone marrow and related morphology. (Parisi, Xenia, and Jacob R. Bledsoe., 2024)
Congenital agranulocytosis arises from genetic defects that disrupt the production, maturation, or survival of neutrophils. Most cases are caused by autosomal dominant or recessive mutations affecting critical pathways in bone marrow stem cells.
ELANE Mutations
ELANE gene mutations are responsible for 50-60% of cases and cause misfolding of neutrophil elastase protein which invokes endoplasmic reticulum stress. This form of stress response impairs normal neutrophil differentiation, inhibiting terminal differentiation at the promyelocyte phase of maturation, resulting in cell apoptosis.
HAX1 Mutations
Mitochondrial membrane stability and apoptosis is controlled by the HAX1 gene. HAX1 mutations result in aberrantly elevated apoptosis of neutrophil precursor cells within the bone marrow, inhibiting maturation to functional neutrophils. HAX1 deficiency is frequently associated with other neurological deficits.
| Therapy | Types | Targets | Mechanism of Action | Development Stage |
|---|---|---|---|---|
| Filgrastim | Recombinant G-CSF | G-CSF receptor | Stimulate neutrophil production | Approved |
| Lenti-ELANE | Lentiviral gene therapy | ELANE gene | Correct mutations in HSCs | Phase I/II trials |
| HAX1 Modulators | Small molecule | HAX1 gene/protein | Reduce apoptosis | Preclinical |
| STAT3 Inhibitors | Small molecule | STAT3 pathway | Reduce ER stress | Preclinical |
| mRNA-ELANE | mRNA-based therapy | ELANE mRNA | Temporary protein correction | 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.
Protheragen offers integrated services in the diagnostics and therapeutics of congenital agranulocytosis leveraging our competencies and advanced technologies. Our attempts to develop effective therapies for congenital agranulocytosis focus on the various molecular pathways responsible for the condition along with targeting the significant unmet medical needs. Protheragen's capability of developing precise disease models allows them to guaranteed thorough testing of safety, efficacy, and mechanism of action of a potential therapeutic candidate.
Protheragen is steadfastly dedicated to meticulously validating and optimizing therapies for congenital agranulocytosis through a thorough series of pharmacodynamics (PD), pharmacokinetics (PK) and toxicology studies. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
References
Myeloproliferative Disorders (MPDs)
Bone Marrow Failure Syndromes (BMFS)
