Updates and advances in pyruvate kinase deficiency

by Selleckchem | Oct 19 2023

Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.

Comments:

Pyruvate kinase (PK) deficiency is a genetic disorder caused by mutations in the PKLR gene. This condition leads to chronic hemolytic anemia, a type of anemia characterized by the destruction of red blood cells. The reduced energy levels in the red cells, which are crucial for maintaining their membrane and function, contribute to the symptoms and complications of the disease.

The clinical manifestations of PK deficiency can vary among individuals, resulting in a range of symptoms and disease severity. This heterogeneity often leads to significant morbidity and can have a negative impact on the overall health-related quality of life for affected individuals.

Historically, treatment options for PK deficiency have been limited to supportive care measures. These include red blood cell transfusions to alleviate anemia and splenectomy (surgical removal of the spleen) to reduce the destruction of red blood cells. However, these treatments do not address the underlying cause of the disease.

Recent advancements have brought about disease-modifying treatment options for PK deficiency. One such option is an oral allosteric PK activator called mitapivat. Mitapivat has been approved for use in adults with PK deficiency and aims to improve the activity of the impaired pyruvate kinase enzyme, thus increasing the production of ATP (adenosine triphosphate) and reducing the symptoms of the disease.

Another potential treatment avenue under investigation is gene therapy, which involves introducing functional copies of the PKLR gene into the patient's cells to restore normal pyruvate kinase function. Clinical trials are currently underway to assess the safety and efficacy of this approach in treating PK deficiency.

Additionally, ongoing studies are exploring the role of PK activators in other congenital hemolytic anemias, expanding the potential treatment options for a broader range of conditions.

To fully understand the long-term effects of disease-modifying therapies like mitapivat and gene therapy, continued evaluation and follow-up studies are necessary. These investigations will provide valuable insights into the efficacy, durability, and potential side effects of these treatments in the management of PK deficiency.