Novel Therapeutics for Bone Marrow Failure Disorders Due to Telomere Exhaustion
Abstract
Background 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 forming system, the bone marrow. Indeed, DC is an inherited bone marrow failure (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 telomerase RNA component (TERC). Based on this work, we developed a hypothesis that blocking one of the proteins in the pathway, called poly(A) polymerase-associated domain containing 5 (PAPD5), would allow us to increase TERC safely, and would restore telomeres and blood cell production. Critical question. The critical question that will be addressed by the proposed research project is whether blocking PAPD5 will increase TERC in cells from DC patients with BMF disorders. We will further address whether this strategy will work on human blood cells which have other problems maintaining their telomeres. Specific BMF disease in question. The specific BMF disease we will research in most of our work will be DC, caused by different genetic mutations. We aim also to research what happens in cells that have been engineered to have short telomeres. Therefore, the research will address various forms of BMF using our novel approach. Innovation. 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. In the past 3 years, we and others have not only identified proteins like PAPD5 as targets for altering TERC but also isolated new drug-like molecules that can block PAPD5. Now we need to test these small molecules for their ability to alter TERC levels and telomeres to cure BMF. Impact. 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 related BMF syndromes. This would be applicable to short telomeres caused by DC gene mutations, and therefore address a large age-range – infants to adults – that get BMF due to DC. More broadly, we expect that restoring the ability of blood cells to divide via TERC could also be applicable to situations in which external factors have caused increased cell turnover and shortened telomeres, such as radiation exposure or chemotherapy. Therefore we expect that this work could provide new cures for BMF patients of a variety of ages, including those of whom other treatments like bone marrow transplant are not an option. Overall, by targeting telomeres, we expect this work will stimulate new avenues in BMF disease research to restore telomeres, blood stem cell division and function, and lead to cures for BMF.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910572
Entities
People
- Suneet Agarwal
Organizations
- Boston Children's Hospital
- United States Army