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Gene Delivery Technology —

The Sleeping Beauty Transposon™ System (SBTS) is a non-viral carrier of genetic information that can insert a gene into vertebrate (human) chromosomes in order to confer a new function or replace a defective gene. Four patent applications regarding the use of this transposon for introducing new DNA into the chromosomes of a cell have been filed, with the base patent* issued in December 2002.
* United States Patent 6,489,458; Hackett , et al. December 3, 2002; DNA-based transposon system for the introduction of nucleic acid into DNA of a cell.

A Novel Gene Transfer System —
The SBTS (SB Therapeutics) shows promise as a long-lasting, safe way to insert genes into the chromosomes of cells without using a viral vector.

The Sleeping Beauty Transposon System is a dynamic biological device
consisting of:

• The SB Transposon.
• The SB Transposase – specific to the SB Transposon.
• A therapeutic gene.

Transposon System Diagram
The Sleeping Beauty transposon carrying the therapeutic gene is "cut" out of the plasmid vector by the engine of this machine (the transposase) and then "pasted" directly into the chromosome. The operation of this biological nano machine is unique and proprietary to DGI.

Discovery Genomics:
• Produces the SB Therapeutic.
• Delivers the SB Therapeutic through either ex-vivo or in-vivo means.
• Licenses the SB Therapeutic to companies for their specific gene-therapy applications.

DGI ADVANTAGES
Non-viral — avoids immunologic reactions associated with viral vectors.
Insulated — proprietary transposon designed to avoid activation of non-target genes.
Life-long therapy — more reliable and sustainable results compared to viral vectors.
Applicable in a broader range of diseases than viral vectors — ability to accommodate genes of many sizes.
Highest activity — of any transposon system used in human cells.
VALIDATED TECHNOLOGY
Demonstrated ability to mediate therapeutic levels of gene expression for long duration in mammals.
SBIR grant to test application of the gene delivery system in Hemophilia A.
SBIR grant to test ex-vivo delivery of the Fanconi Anemia Fanc-C and Fanc-A genes in collaboration with MaxCyte, Inc.
Strategic Collaboration with R&D Systems/TECHNE Corporation.
PATENT STATUS
Patent covering method and use issued December 2002.
Patents covering specific applications for the gene delivery method filed.

SEE RELATED ARTICLES

Gene Therapy —
Gene therapy is designed to treat, cure, and ultimately prevent diseases and disorders by inserting corrective genes into the chromosomes of selective tissues in a human. As a result, a patient’s cells manufacture proteins that will correct either an inborn genetic disorder, such as hemophilia, or protect against an acquired disease, such as cancer or AIDS. Gene carriers, called vectors, deliver therapeutic genes to a patient's cells.

(use the buttons to play this animation)
The Sleeping Beauty Transposon System is a leading, long-lasting way to insert genes into the chromosomes of cells without using a virus. Gene therapy uses a patient’s cells to manufacture proteins that will correct either an inborn genetic disorder or an acquired disease, such as cancer, by inserting a gene into the patient’s chromosomes.


International validation has shown the original SBTS
to be 10-fold more active than others.

S.E. Fischer, et al. (2001) PNAS 98: 6759 [Europe]; K. Horie et al. (2001) PNAS 98: 9191 [Japan]; A.J. Dupuy et al. (2002) PNAS 99: 4495 [USA]

DGI expects its SB Therapeutics to possess several safety and efficacy advantages over viral vectors. The SB Therapeutic is non-viral and thus does not incur the immunological reactions frequently associated with viral vectors. DGI has developed a proprietary Activation-Safe Transposon™ that it expects will avoid the possibility of unintentionally activating other genes, which has been a concern in some gene therapy trials. Although we do not anticipate integration of the Transposase gene, we have inserted it into mice and have seen no adverse effects over several generations involving hundreds of mice. 

DGI's Gene Therapy Targets for SB Therapeutics —

Fanconi Anemia:
DGI is planning to conduct a clinical trial to test the use of the SB Therapeutic for treatment of Fanconi Anemia. This trial will be conducted at the University of Minnesota under the direction of world-renowned experts in therapies for Fanconi Anemia. DGI will provide the most advanced transposon technology for this trial, as well as arrange for the manufacturing of clinical-grade DNA for the treatments. The Fanconi Anemia Research Fund will provide the gene to be inserted. We anticipate that this clinical trial will be initiated within two years, six years earlier than we had previously believed likely for testing in humans. Participating in the Fanconi Anemia trial is important for DGI because it:

Permits us to apply for an IND for a combined Phase I/II clinical trial that will establish a significant development milestone.
Demonstrates proof of principle for the effectiveness of the SB Therapeutic in the treatment of diseases, such as hemophilia A and AIDS, by gene transfer into hematopoietic cells. Hemophilia A and B can also treated in-vivo.
Is applicable to a wide variety of genetic diseases.

Hemophilia A:
DGI has received an SBIR grant to evaluate the SB Therapeutic as a safe cure for hemophilia A. Hemophilia A is a bleeding disorder caused by the absence of clotting Factor VIII (FVIII). This disease is inherited and it is estimated that there are 20,000 affected individuals in the U.S. Treatment of Hemophilia A has been greatly improved over the last 10 years with the availability of recombinant FVIII. However, the high expense of this treatment and variable levels of FVIII maintained in the circulation compromise the effectiveness of this enzyme-replacement therapy. Moreover, the FVIII gene is too large for current viral vectors. Our approach is based on preliminary studies at the University of Minnesota, Stanford University, and elsewhere that demonstrated long-term, SB Therapeutic-mediated gene expression. Results from these experiments support subsequent evaluation of the SB Therapeutic in dogs as part of a Phase II SBIR study.

Hemophilia B (while not in our current business plan, licensing opportunities are encouraged):
Hemophilia B, a blood clotting disease, results from a deficiency in the Factor IX gene protein. The SB Therapeutic has been shown to deliver human Factor IX genes into chromosomes of liver cells in Factor IX-deficient mice at sufficient rates to confer therapeutic levels of the human blood coagulation Factor IX protein. These mice, which are a model of human hemophilia B, retained blood-clotting ability for the rest of their lives. (Studies conducted by Mark Kay at Stanford University, published in Nature Genetics in 2000.)

DGI SB-THERAPEUTICS PIPELINE

Current Focus

(Orphan Diseases)
Disease Gene Market DGI Advantages
Fanconi Anemia
(ready for clinical trials)
Fanc-C &
Fanc-A
>$300 M IND & Orphan Drug filing in progress; SBIR funding; patients available.
Hemophilia A

 

Factor VIII >$500 M SBIR funding; DGI partners.
(Orphan Disease) Brain Tumors IL13-HSVTK $2 B/yr Founder's discovery

R & D

Cancer

 

EC2-peptide* $4-5 B/yr Patent filed.
Ischemia

 

AN1*, SRP1*, AN2*, EC1*, EC2* $10 B/yr Patents filed.
AIDS

 

siRNAs >$10 B/yr
* DGI Proprietary Patent Pending Biologicals
Licensing —
As an early-stage company we seek to enter into license agreements and/or collaborations with others to test, perfect and use our SB Therapeutics in clinical applications of gene therapy.

 


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