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CMCC 2925

PAPD5 inhibitors to treat telomere diseases

Inventors: Suneet Agarwal, Dianne Moon, Baris Boyraz, Matthew Segal

Invention Types: Therapeutics

Research Areas: Cardiovascular/Cardiology, Genetic Disease, Oncology/Hematology

Keywords: Assay, Drug Screening, Heart Disease

For More Information Contact:  Meyer, Abbie

 

Invention Description:

Telomeres are distinctive DNA structures that protect the ends of each chromosome strand that provides genome stability. During cell division, telomeres are critical to allow proper DNA replication and prevent chromosomal end fusion. The enzyme telomerase repairs and preserves the length of telomeres during cell division. The telomerase RNA component (TERC) is a non-coding RNA template for telomerase and TERC levels are critical determinant for self-renewal. Short telomere length due to genetic or acquired insults (i.e., aging and environmental toxins) result in a loss of cellular self-renewal capability and leads to life-threating diseases such as dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, bone marrow failure and increased risk of cancer. Currently there is a lack of effective medical therapies to treat these telomere diseases.


Dr. Agarwal and collaborators found that mutations in poly(A) ribonucleases (PARN) gene limits the biogenesis of TERC, decreasing telomerase activity, and compromising cellular self-renewal. Telomerase deficiency due to PARN mutations can be rescued by inhibiting the non-canonical poly(A) polymerase PAPD5 (PAP Associated Domain Containing 5). These findings using primary patient cells indicate that PAPD5 and PARN mediate opposing and non-redundant effects in the posttranscriptional maturation of nascent TERC RNA transcripts. Therefore, Dr. Agarwal’s team proposes the use of therapeutic agents targeting PAPD5 and PARN to modulate TERC levels, telomerase activity, telomere length and cellular self-renewal.

Applications:

• Use of PAPD5 inhibitors to treat dyskeratosis congenita, aplastic anemia/bone marrow failure, and pulmonary fibrosis.

• Use of PARN inhibitors to treat cancer.

• Biomarkers to develop companion diagnostics tools for telomere diseases.

Competitive Advantages:

Well characterized targets able to modulate TERC biogenesis and telomerase activity to impact cellular self-renewal.

Business Opportunity:

Licensing agreement or sponsored research, including proprietary high-throughput screening assays for hit ID.

Key Publications: 1. Moon DH, Segal M, Boyraz B, Hofmann I, Guinan E, Cahan P, Tai AK, Agarwal S. Poly(A)-specific ribonuclease (PARN) mediates 3′ end maturation of the telomerase RNA component. Nature Genetics, 47(12):1482-8, 2015.


2. Boyraz B, Moon DH, Segal M, Muosieyiri MZ, Aykanat A, Tai AK, Cahan P, Agarwal S. Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease. J Clin Invest. 2016 Sep 1;126(9):3377-82. doi: 10.1172/JCI87547. Epub 2016 Aug 2.

IPStatus: Pat. Pend.