Precision Medicine for telomere pathologies
and age-related disorders
Telomere dysfunction is at the root of many human diseases
TELOBLOCK is our solution to inhibit cellular senescence induced by pathogenic telomeres with unprecedented specificity.
Telomeres are essential for maintaining chromosomal integrity.
When telomeres shorten and get damaged with aging, the DNA Damage Response (DDR) is triggered. As a consequence, cells stop proliferating and enter cellular senescence, spreading inflammation and promoting fibrosis and tissue dysfunction.
TELOBLOCK acts by inhibiting the DDR selectively at short and damaged telomeres, without altering telomere length.
TELOBLOCK
An antisense nucleotide against RNAs produced at short or damaged telomeres
A pioneering approach developed by our scientific founder and group leader at IFOM (FIRC Institute of Molecular Oncology) Fabrizio d'Adda di Fagagna in Milan, Italy
TELOBLOCK has therapeutic effect in numerous disease models:
Telomere Biology Disorders (TBD) or Short Telomere Syndromes (STS)
TBD/STS are the most prevalent premature aging syndromes and are caused by inherited mutations in genes responsible for telomere integrity. The most affected organs are the lungs, bone marrow, spleen, gastrointestinal tract, and skin.
The most common clinical presentations are familial IPF (Idiopathic Pulmonary Fibrosis), bone marrow failure, aplastic anemia, and dyskeratosis congenita.
TELOBLOCK reduces and reverts lung pathology in a genetic mouse model of IPF, and improves hematopoiesis and stem cells fitness in mice models of bone marrow failure, dyskeratosis congenita and aplastic anemia.
Idiopathic Pulmonary Fibrosis
IPF is a progressive degenerative lung disease causing fibrosis of the lungs. There is currently no cure for IPF, and the available treatments only delay the need for lung transplantation.
IPF is strongly linked to telomere dysfunction. One-quarter of IPF patients present with short telomeres (below 1 percentile of telomere length of the general population).
TELOBLOCK stops and reverts the progression of lung fibrosis and improves lung tissue architecture in a translational genetic mouse model of IPF caused by short telomeres.
Ex-vivo adjunct therapy
Re-plenishing immune cells to patients is a key approach in organ transplantation and cancer chemotherapy following immune suppression, most often done as bone marrow transplantation. Personalized cancer treatments and immunotherapy (e.g. CART) require manipulation of patients' own immune cells, which are modified and amplified outside the body and then infused back to the body. Such approaches are less effective in patients with short telomeres and the elderly.
TELOBLOCK increases the proliferative fitness of human hematopoietic cells from healthy aged individuals upon transient ex-vivo treatment and offers the opportunities to enhance therapeutic effectiveness of autologous or heterologous bone marrow transplantation and immune cell-based cancer therapies.
Successfully completed the Danube Labs preclinical acceleration program
Danube Labs is a partnership between CEBINA, Evotec, and Danube BioVentures.
The TELOBLOCK technology was validated and confirmed to be suitable for product development.
TAG Therapeutics is supported by
Selected Publications:
-
Guidelines for minimal information on cellular senescence experimentation in vivo
Ogrodnik et al, Cell. 2024 Aug 8;187(16):4150-4175. -
Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs
Rosso et al, Nat Commun. 2023 Nov 4;14(1):7086. -
Telomere dysfunction in ageing and age-related diseases
Rossiello et al, Nature Cell Biology volume 24, pages 135–147 (2022) -
DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging
Sepe et al, EMBO Rep. 2021 Dec 2;e53658. Online ahead of print. -
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco et al, Nature Reviews Molecular Cell Biology (2020) -
Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Aguado et al, Nature Communications volume 10, Article number: 4990 (2019) -
Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors
Pessina et al, Nature Cell Biology volume 21, pages1286–1299 (2019) -
Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks.
Michelini et al, Nat Cell Biol. 2017 Dec;19(12):1400-1411. Epub 2017 Nov 27. -
DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs
Rossiello et al, Nature Communications 8, Article number: 13980 (2017) -
Site-specific DICER and DROSHA RNA products control the DNA-damage response
Francia et al, Nature (2012) -
Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation.
Fumagalli et al, Nat Cell Biol. 2012 Mar 18;14(4):355-65. -
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna F., Nature Reviews Cancer 8, 512-522 (July 2008) -
Cellular senescence: when bad things happen to good cells.
Campisi et al, Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40. PMID: 17667954 -
A DNA damage checkpoint-mediated response in telomere-initiated senescence.
d'Adda di Fagagna et al, Nature 2003; 426: 194-8
