CD22ΔE12-siRNA nanoparticle
Credit: Fatih Uckun
Researchers have identified a molecular target for RNA interference (RNAi) therapy, and they believe that, by targeting this molecular lesion, they may be able to eliminate drug resistance in B-lineage acute lymphoblastic leukemia (ALL).
“We knew that we could kill chemotherapy-resistant leukemia cells if we only knew what made them so resistant,” said study author Fatih Uckun, MD, PhD, of the Children’s Hospital Los Angeles in California.
“Once we determined the mechanism, the next step was obvious—to rationally design a drug that would take out that specific target.”
The target is a defective gene that results in the production of abnormal CD22—CD22ΔE12. The researchers found that pediatric and adult B-lineage lymphoid malignancies are characterized by a high incidence of CD22ΔE12.
The group’s experiments revealed a causal link between CD22ΔE12 and the aggressive biology of B-ALL cells. When the researchers knocked down CD22ΔE12 in primary B-ALL cells using small interfering RNA (siRNA), they observed inhibition of clonogenicity.
The team therefore theorized that the siRNA-mediated depletion of CD22ΔE12 might be useful for treating B-ALL.
So they designed a nanoparticle formulation of CD22ΔE12-siRNA in which a polypeptide functions as the delivery system. The particle has a diameter of 100 nanometers.
Experiments showed that the nanoparticle could deliver its siRNA cargo into the cytosol of ALL-1 cells, thereby depleting CD22ΔE12 and inhibiting leukemic cell growth in vitro.
The researchers said that further development of this nanoparticle or other nanoformulation platforms for CD22ΔE12-siRNA could facilitate an effective therapeutic RNAi strategy to treat aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.
“The goal is to translate our recent research discoveries in nanotechnology and biotherapy into effective patient-tailored treatment programs for the most common form of childhood cancer,” Dr Uckun said.
He and his colleagues described this research in EBioMedicine.
