Funds for innovative gene therapy

Two Hutchinson Center researchers will share in a new $23.7 million grant awarded to Seattle Children's Hospital Research Institute to support the Northwest Genome Engineering Consortium. Drs. Hans-Peter Kiem, in the Clinical Research Division, and Barry Stoddard, in the Basic Sciences Division, together will receive $5.2 million over the life of the National Institutes of Health grant, which will fund the development of new methods for gene repair.

Funding comes from the NIH Roadmap for Medical Research, a new type of federal grant program that addresses especially complex problems in research that require expertise across multiple scientific disciplines. The Northwest Genome Engineering Consortium (NGEC) comprises 11 projects that will build upon each other to develop methods for gene repair, an innovative approach to gene therapy.

Gene repair involves manipulating defective sequences of DNA in a targeted gene to change them to the correct sequence, restoring the gene to normal function and eliminating the cause of inherited disease. Gene repair requires multiple scientific disciplines to generate new kinds of proteins that can perform the required manipulations and then deliver them to a patient's diseased tissues.

"With this research we hope to develop new and efficient approaches for gene repair in certain types of stem cells and other tissues, and use these methods to improve treatments for genetic diseases affecting these tissues," said Dr. Andrew Scharenberg, project lead at Children's.

While gene repair ultimately may be useful against a wide range of diseases, Scharenberg and colleagues believe single-gene inherited disorders of the lymph and bone-marrow systems such as immune deficiencies, sickle-cell disease and thalassemias are the best place to start. Collectively, these disorders are a major disease burden in children worldwide. The target cells in these diseases that will be manipulated by the gene-repair process are blood stem cells, and they are readily accessible. By working with these disorders, the NGEC will build upon Seattle's strong regional expertise and reputation in this type of stem-cell repair.

Safe gene therapy/repair

Kiem said the overall objective of this project is to study homing endonuclease-based hematopoietic stem cell (HSC) gene-repair strategies in a clinically relevant animal model to improve and evaluate various HSC gene-transfer systems to treat conditions ranging from X-linked severe combined immunodeficiency (XSCID) to pyruvate kinase (PK) deficiency.

"The development of leukemia in four children with XSCID after HSC gene therapy with a gammaretroviral vector has demonstrated the risks of retrovirus-mediated gene therapy. Thus, the development of site-specific gene replacement/gene repair strategies with reduced risks of insertional mutagenesis has become a crucially important goal for the development of safe gene therapy/repair approaches in patients with genetic disorders," Kiem said.

Stoddard said, homing endonucleases are used in the gene-repair approach because they are extraordinarily specific DNA-binding proteins that recognize and act at individual sites within a host genome.

"These proteins are under intense study for the purpose of engineering reagents to be used for gene therapy and other applications," said Stoddard, whose laboratory has made major contributions to the understanding of homing endonucleases, from determining their structure and mechanisms to creating artificial variants of these proteins for use in gene therapy.

Three University of Washington researchers also are part of the Children's grant.