Research grant for novel gene therapy for Shwachman-Diamond syndrome

Sanquin researcher Despoina Trasanidou has been awarded a Veni grant for research into a novel form of gene therapy for hereditary blood disorders. Her initial focus is on Shwachman-Diamond syndrome (SDS), a rare inherited disorder in which patients produce too few blood cells due to a genetic defect. A Veni grant is awarded by the Dutch Research Council (NWO) to talented early-career researchers. 

SDS is caused by a mutation in the SBDS gene. As a result, protein production in cells is disrupted, particularly affecting rapidly dividing cells such as blood-forming cells in the bone marrow. Patients may develop anemia, severe infections, and an increased risk of bleeding. Problems affecting the pancreas, growth, and bone development are also common. There is currently no targeted treatment for SDS. In severe cases, hematopoietic stem cell transplantation is the only treatment option. 

Over the past several years, a number of gene therapies have been developed for blood disorders. In these approaches, hematopoietic stem cells are collected from the patient, genetically modified in the laboratory, and then returned to the body. While effective, this process is complex, costly, and burdensome for patients. 

Correct stem cells within the body

Trasanidou aims to develop a different approach. Rather than correcting stem cells outside the body, she wants to repair hematopoietic stem cells directly within the body. To achieve this, she uses lipid nanoparticles that carry genetic instructions. To ensure these instructions reach the correct cells, she is developing specialized nanobodies: small proteins that recognize and bind to blood stem cells. These nanobodies are attached to the lipid nanoparticles, enabling the genetic machinery to be delivered specifically to hematopoietic stem cells. 

The genetic instructions contain components of CRISPR technology, which can be used to precisely correct a disease-causing DNA mutation. Within the project, Trasanidou is developing an approach to repair the most common mutation found in SDS. The strategy will first be tested in cultured cells and patient-derived blood stem cells, after which its ability to work directly in the body will be investigated. 

Applicable to other blood diseases

A major goal of the project is the development of a broadly applicable platform for in vivo gene therapy of blood disorders. SDS serves as the first proof of concept. If successful, the same technology could potentially be applied to other hereditary blood disorders in the future.

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