IND-Enabling Studies of Polymerase Inhibitors for BMF Due to Telomere Exhaustion
Abstract
Overall Objective: The proposed research aims to develop a drug that can be taken by mouth to cure bone marrow failure (BMF) in patients with dyskeratosis congenita (DC), and possibly other forms of BMF. The FY22 BMFRP Investigator-Initiated Research Award Focus Area to be addressed is to find effective BMF treatments and cures. The lead therapeutic candidates to be further developed are compounds that inhibit the protein PAPD5. Background, Rationale, and Hypothesis: Human cells can only divide and replenish themselves a certain number of times. This is in part due to the length of telomeres, DNA repeats at the ends of chromosomes, which shorten every time a cell divides. When telomeres get short enough, the cell stops dividing. In this way, telomeres can be thought of as a clock keeping track of when cells need to stop dividing. There are a variety of external factors, including inflammation, injury, chemotherapy, and radiation, that can cause cells to turn over faster in the process of healing and result in short telomeres. In rare cases, there are also genetic mutations that cause telomeres to shorten sooner than usual, resulting in a disease called dyskeratosis congenita (DC). In both cases, one of the most sensitive tissues is the blood system, the bone marrow. Indeed, DC is an inherited BMF disease. Short telomeres are also associated with other forms of BMF including aplastic anemia and myelodysplastic syndrome (MDS). If telomeres could be elongated safely, it might provide a way to help blood stem cells keep dividing as a way of restoring function and curing BMF diseases. Recently, by studying genetics in DC patients, we discovered a new pathway in cells that controls one of the molecules that is critical for making telomeres longer, called TERC. Based on this work, we developed a hypothesis that blocking one of the proteins in the pathway, called PAPD5, would allow us to increase TERC safely and would restore telomeres and blood cell production in patients with DC and other forms of BMF. We went on to discover new small molecules (i.e., drug prototypes) that inhibit PAPD5 and are able to increase TERC and lengthen telomeres in cells from DC patients. Because we have shown that the telomeres in DC patient cells are restored by these molecules, we predict that the blood system could be replenished and BMF successfully treated if such a molecule were used as a drug. Applications and Disease Targets: In this proposed research, our goal is to use a variety of methods to test which ones of our drug prototypes have the most promise as actual drugs to be used by patients with BMF. The specific BMF disease we will study in most of our work will be DC, which is caused by a number of different genetic mutations. However, because short telomeres are found across different types of BMF, it is also possible that the ultimate applicability of the research extends beyond DC. The research is innovative because the concept of inhibiting PAPD5 to increase TERC is completely unexpected. It has been revealed only very recently by genetic studies done by our lab and independently validated by others. Previously there were no clues about how to change TERC levels to increase telomeres. If these studies are successful, they could open up a whole new way to treat BMF disorders, namely by increasing TERC and telomeres in DC and other BMF syndromes. This would be applicable to patients with short telomeres across a large age range - infants to adults - that gets BMF due to mutations that cause short telomeres. More broadly, we expect that restoring the ability of blood cells to divide via TERC could be applicable to situations in which external factors have caused increased blood cell destruction, such as radiation exposure or chemotherapy. Therefore, we expect that this work could provide new cures for BMF patients beyond DC. In summary, the proposed project focuses on a new approach to restore blood cell d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310932
Entities
People
- Suneet Agarwal
Organizations
- United States Army