A number of diseases arise due to defects in bone marrow cells. Such conditions may be treated through bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) is a major complication that can occur after BMT. The transplanted cells from the donor (graft) treat the cells of the patient (host) as “foreign.” Instead of helping the recipient, the immune cells from the donor graft attack the host’s cells, tissues and organs, as if fighting an infection. Acute GVHD soon after transplantation can be mild, moderate or severe; it can even fatal if not controlled. The disease may also present as a later-onset chronic condition. Therapy for chronic GVHD is associated with a lifetime of immune-suppressive drugs that can have long-term side effects and toxicities. The preimplantation factor (PIF), a peptide normally present during early stages of viable pregnancy, has been shown to protect against GVHD. The aim of this project was to continue development of PIF to prepare it for human trials in GVHD patients.
BMT is a well-established approach for treating malignant and non-malignant hematopoietic diseases, although it is considered a last resort. Even when matched donors are used, many patients develop GVHD, which, when not fatal, can progress to a chronic, lifelong condition. Symptoms of GVHD can involve a number of tissues and organs, including the skin, hair, lungs, liver and gastrointestinal tract. Current treatments include immunosuppressive agents and steroids, although these regimens do not work for all patients. Effective, non-toxic, long-term treatment for chronic GVHD is imperative.
PIF is an evolutionarily conserved peptide that accompanies and supports viable embryo development, regulating inflammation, immunity and transplant acceptance. PIF has been shown to regulate several pro-inflammatory genes and proteins, block activated T-cell proliferation, and reduce oxidative stress.
In this project, synthetic PIF (sPIF) activity in the GVHD context was assessed after BMT. Short-term, low-dose administration of sPIF in preclinical models was shown to promote and sustain engraftment of donor bone marrow cells, prevent the development of GVHD, preserve the beneficial graft-versus-leukemia effect and significantly reduce overall mortality. sPIF treatment led to protection against dermatitis, hepatitis and colon ulceration, the three classic hallmarks of GVHD. sPIF treatment also reduced mortality following allogeneic BMT from an unrelated donor and promoted long-term cellular engraftment in syngeneic transplant from a genetically identical donor. These findings suggest that PIF could be useful against the range of acute and chronic adverse effects that develop after BMT, possibly making the overall procedure more feasible rather than a last resort.
BioIncept, LLC, Cherry Hill, NJ
Eytan Barnea, M.D.
Public Health Impact
Each year, approximately 20,000 people undergo bone marrow transplantation in the United States. Most patients in need of transplantation do not have a matching donor in their family, increasing their likelihood of GVHD after receiving BMT from an unrelated source. sPIF has the potential to reduce the long-term, multi-organ complications of GVHD as an effective, non-toxic alternative to current therapies. Beyond GVHD, this project represents a “many diseases at a time” approach, in light of additional preclinical data generated by the collaborators. Leveraging the data developed by BrIDGs toward GVHD, the lead collaborators are moving into additional therapeutic indications, including mitigation of radiation-induced gastrointestinal damage and traumatic brain injury.
The BrIDGs team completed the IND-directed studies that will form the basis of a regulatory filing by the collaborators at BioIncept to begin clinical trials.
- Synthesis of Good Manufacturing Practice (GMP) material
- Investigational New Drug-directed toxicology