By Morgan Alford, Graduate Student, Hancock Lab
Beta-thalassemias are a group of inherited blood disorders caused by a decrease in beta hemoglobin chains that can result in severe anemia, reduced oxygen supply to tissues, failure to thrive, and death. Blood transfusions are the most common form of treatment for these disorders. However, since humans cannot remove iron from the body, reactive iron from repeated transfusions accumulates and causes organ dysfunction. Therefore, iron chelation therapy is given alongside transfusions to bind iron and promote its excretion. Deferoxamine, the gold-standard iron chelator currently on the market, effectively reduces the concentration of reactive iron in serum following blood transfusion, but the drug has a short circulation time, and can cause neurotoxicity, nausea, diarrhea and abdominal pain when taken long-term. These adverse effects, together with an intense blood transfusion regimen (7 hrs, 5-6 times per week), likely contribute to the high rate of noncompliance. Clearly, there is a need for the design of safer alternative chelating agents.
A recent study by Dr. Srinivas Abbina and colleagues in the Kizhakkedathu lab in the Centre for Blood Research (CBR) at UBC shows that adverse effects of Deferoxamine can be ameliorated by molecular conjugation to a bulky class of chemicals called biodegradable hyperbranched polyglycerols. The design of the conjugated molecule determines the degree of improvement in iron circulation and excretion following chelation. More specifically, iron chelation efficiency depends on the biodegradable linkages used in conjugation. For example, more stable conjugates that have a high degree of linkage require more time to be broken down and are associated with prolonged iron excretion from the liver and kidneys. All conjugates presently studied in vitro degraded under acidic conditions that are characteristic of the environment in vivo. Moreover, none of the conjugates were toxic to liver or fibroblast cells. Consistent with studies performed in synthetic media, conjugates were degraded between 8 and 70 hrs after administration in a mouse model of iron overload (depending on degree of linkage): Faster degradation was associated with lower iron accumulation in all organs and iron was excreted via two different pathways in a similar time. In contrast, slower degradation was associated with greater accumulation in the spleen and pancreas and favoured excretion via the kidneys.
In this study, Abbina et al. demonstrate, for the first time, the therapeutic potential of conjugated drugs for promotion of iron excretion and reduction of iron accumulation in vital organs. It is hoped that this therapeutic approach will not only have improved efficacy as compared to the current gold-standard chelator Deferoxamine, but the anticipated reduced incidence and severity of side effects should increase compliance.
We will watch expectantly for good news for patients with disorders that cause iron overload, as these novel drugs hopefully enter the clinic in the near future!
- Abbina S, Abbasi U, Gill A, Wong K, Kalathottukaren MT, Kizhakkedathu JN. 2019. Design of safe nanotherapeutics for the excretion of excess systemic toxic iron. ACS Cent Sci 5(5):917-926. doi: 10.1021/acscentsci.9b00284.