Triplex-mediated DNA repair as a novel therapy for Hurler Syndrome patients

Award Information
Department of Health and Human Services
Award Year:
Phase I
Agency Tracking Number:
Solicitation Year:
Solicitation Topic Code:
Solicitation Number:
Small Business Information
BOX 8175, NEW HAVEN, CT, -
Hubzone Owned:
Minority Owned:
Woman Owned:
Principal Investigator:
(203) 503-0383
Business Contact:
06511 J
(203) 393-9439
Research Institution:

DESCRIPTION (provided by applicant): This is a proposal to test the feasibility of using triplex molecules for use as a therapeutic to correct Hurler Syndrome (HS). Lysosomal storage diseases (LSDs), such as HS, represent a diverse collection of monogenicdisorders that have devastating clinical features. LSDs are caused by mutations in genes that encode lysosomal enzymes and other proteins that are critical for lysosomal function. HS is caused by mutations in the -L-iduronidase gene (IDUA). For many LSDs, treatment consists of enzyme replacement therapy and supportive care. However, enzyme replacement therapy costs from 90,000 to 565,000 per patient. Alternatively, allogeneic hematopoietic stem cell transplantation (HSCT) represents a highly effective treatment. However, allogeneic HSCT requires an HLA-matched donor, is associated with significant morbidity and mortality and is expensive, about 200,000 per patient. Genetic modification of autologous HSCT, using CD34+ cells, is emerging as a viable therapeutic alternative to allogeneic HSCT. Autologous HSCT is preferred because it is far less expensive and safer than allogeneic HSCT. One emerging approach to targeted genome modification in CD34+ cells is the use of triplex molecules, either in the formof triplex-forming oligonucleotides or peptide nucleic acids. These molecules bind to duplex DNA in a sequence-specific manner and stimulate recombination when combined with donor DNA molecules. Gene modification occurs via recruitment of the cells own DNArepair machinery, without the need for viral vectors. Viral vectors have proven problematic in such therapies. Our Specific Aim is to test the feasibility of using triplex molecules to correct one of the most prominent gene mutations in the IDUA gene, W402X. For this technology to be viable as a commercial therapy, we must demonstrate that we can achieve a success rate of at least 3% for correction of our gene target in CD34+ cells. Next, we must demonstrate that we can generate a sufficient number of monocytes from these stem cells to be utilized as part of a bridging therapy to wholesale HSCT. In Phase II, we will carry out in vivo studies to demonstrate in vivo efficacy and work on developmental and IND enabling studies to move this technology toward clinical studies. PUBLIC HEALTH RELEVANCE: Hurler Syndrome (HS), a devastating genetic disease that results in multiple organ failure with progressive deterioration in the central nervous system, is caused by mutations in a single gene that is involved in the processing of large sugar molecules within compartments in our cells. L2 Diagnostics LLC is proposing to develop a therapeutic gene targeting protocol to correct one of the most prominent mutations responsible for HS. Our protocol would repair this mutation in isolated blood stem cells from HS patients and then reintroduce the corrected cells back into the patient with the potential of having a significant impact on the symptoms of the disease.

* information listed above is at the time of submission.

Agency Micro-sites

SBA logo

Department of Agriculture logo

Department of Commerce logo

Department of Defense logo

Department of Education logo

Department of Energy logo

Department of Health and Human Services logo

Department of Homeland Security logo

Department of Transportation logo

Enviromental Protection Agency logo

National Aeronautics and Space Administration logo

National Science Foundation logo
US Flag An Official Website of the United States Government