Dear Ms.

Stafford, On February 27-28, constituents from Congressman McHenrys region of North Carolina were in Washington as part of the Hemophilia Advocacy Effort. Brad Nolan of HomeCare for the Cure was one of the constituents, and met with Congressman McHenry. Mr. Nolan has 2 sons with hemophilia A, and has been working with our group at the Wake Forest Institute for Regenerative Medicine to try to raise money for our ongoing research, which we feel has the potential to provide a permanent cure for hemophilia A. Mr. Nolan shared with us that, when he discussed our ongoing work, Congressman McHenry told him that he would like to be provided with a white paper providing an overview of the science behind our ongoing work, as he felt that this type of work should be receiving support. The document we prepared follows this letter. I would appreciate it greatly if you could confirm receipt of this information, and please let me know if any further information is required. Thank you for your time and consideration. Sincerely, Christopher D. Porada, Ph.D. Associate Professor Wake Forest Institute for Regenerative Medicine Richard H. Dean Biomedical Building, 4th Floor 391 Technology Way Winston-Salem, NC 27157-1083 E-mail:cporada@wakehealth.edu

The Challenge: Hemophilia A is a disease that affects the ability of the blood to clot, leading to frequent, generalized bruising, external and internal bleeding, debilitating joint disease, a markedly reduced quality of life, and early death. Hemophilia A is caused by a deficiency in a protein in the body (Factor 8) that promotes coagulation, which is the ability of blood to clot, Factor 8, and is the most common inheritable deficiency of blood clotting, affecting over 400,000 people around the world. Hemophilia A, Current treatment consists of Factor 8injections of the protein Factor 8 three times a week for the patients entire life. While this treatment has greatly improved quality of life for many Hemophilia A patients, it is far from ideal, due to the need for lifelong infusions and the high treatment cost (often >$300,000/yr). In addition, this therapy is not available for ~75% of the worlds hemophiliacs. Even among those lucky enough to have access to current treatments and the means to afford them, there is still no guarantee of a lifetime of successful outcomes, since roughly 30% of patients receiving the current Factor 8protein products ultimately mount an immune response to what their body sees as a foreign entity, and develop antibodies to Factor 8, referred to as inhibitors. The formation of these inhibitors

greatly complicates the management of bleeding in these patients, and further increases the already staggering treatment cost. There is thus a critical unmet need to develop new Hemophilia A therapies offering longerlasting benefit or permanent cure. Even if the cost of current therapies were reduced sufficiently that the majority of Hemophilia A patients could afford the protein infusions, these therapies would still be plagued by treatment failure due to the inhibitors. This problem could likely be circumvented by performing treatment before birth.

The Solution: A clinically viable treatment option for inherited diseases, which has been safely performed for decades in humans, is in utero cell transplantation (IUT). To date, 46 IUTs have been performed in human patients for 14 different genetic disorders, and have proven, beyond doubt, its feasibility and safety. By allowing correction prior to disease onset, IUT is one of the few therapies that can promise the birth of a healthy infant. Indeed, todate, IUT has provided complete cure in at least 10 human patients.

Prenatal diagnosis for Hemophilia A is feasible, available, and is encouraged for individuals with a family history of the disease, giving the opportunity to intervene therapeutically during the early development period. While most individuals with a family history of Hemophilia A are encouraged to have prenatal screening, parents currently have only 2 choices following prenatal diagnosis of Hemophilia A: termination of pregnancy or the birth of an affected child. If successfully applied to Hemophilia A, IUT could promise the birth of a healthy infant who required no further treatments, greatly improving quality of life, and removing the heavy psychological and monetary burden on the patients, their families, and the health care system.

Using sheep as a preclinical animal model, many investigators have demonstrated that IUT of modified bone marrow cells results in robust and stable organ engraftment, long-term expression of the inserted protein drivers (genes carried with the bone marrow cells), and release of the secreted and needed proteins into the circulation, all without an immune response.

In order to avoid immune rejection, scientists have reported that exposure to vectorspecific proteins (including coagulation factors) during early development induces stable, lifelong immune tolerance. These findings suggest that IUT would be ideal for treating a disease like Hemophilia A, since it could induce lifelong tolerance to Factor 8. Recently, using a strategy of injecting modified bone marrow cells into a novel experimental model, scientists at the Wake Forest University were able to successfully cure two pediatric sheep with Hemophilia A, with complete prevention of their frequent spontaneous bleeds, reversal of their crippling joint disease, and their

return to normal physical activity. The modified bone marrow cells led to the persistent production of the protein Factor 8. This work provides compelling evidence that the transplantation of Factor 8-expressing BMMSC could be curative for Hemophilia A. Further work and resources are needed to complete the proof of principle studies that would lead to human application. The use of the unique Hemophilia A model and IUT developed at Wake Forest can be used to test the ability of using modified bone marrow to achieve the cure for Hemophilia A, and without the current immune hurdles, by the time of birth.