HaplnScience

SCIENCE

SCIENCE

Aging and Diseases
  • Human body is constantly receiving harmful stimuli from the surrounding environment and has the ability to maintain homeostasis as a defense mechanism against it. Aging means that the function of maintaining homeostasis of human tissues/organs is gradually deteriorated or destroyed by being repeatedly exposed to various environmental substances and several harmful factors such as ultraviolet rays. The mechanism of aging known so far is that the number of aged cells increases due to cell damage that inevitably continues with aging, and the Senescence-Associated Secretory Phenotype (SASP) they release adversely affects not only themselves but also normal un-aged cells or tissues around them. It eventually leads to aging in the organs and the entire body.
  • 'Cell damage,' the core concept of the aging mechanism, means a phenomenon in which major signaling pathways and functions within a cell are gradually lost in complexity, and complementary amplification pathways between cell damage and aging are intricately entangled. In general, it refers to the damage to the crosstalk mechanism between the intracellular/extracellular matrices or cells, the damage to the genome including DNA, the damage to the mitochondria which is an energy production plant, and the damage to the cleaning mechanism of unnecessary proteins or metabolic debris, and others. In most cases, this phenomenon of complementary amplification between cell damage and aging leads to disease.
  • Age-related diseases that rapidly increase having aging as a major risk factor are arthritis, chronic obstructive pulmonary disease, cardiovascular disease, cancer, type 2 diabetes, Alzheimer1) and etc. The incidence of these diseases increases exponentially with age2), and 100,000 people die every day from age-related diseases around the world3). These age-related diseases are the major problems of a global trend aging population and are the top priority that must be overcome for the health and future of humankind.
References
  • 1) MacNee, William, Roberto A. Robinovich, and Gourab Choudhury. “Aging and the border between health and disease.” (2014)
  • 2) Belikov, Aleksey V. "Age-related diseases as vicious cycles." Ageing Research Reviews 49 (2019)
  • 3) De Grey, Aubrey DNJ. "Life span extension research and public debate: societal considerations." Studies in Ethics, Law, and Technology 1.1 (2007)

SCIENCE

Role of ECM
  • ECM (Extracellular Matrix) is complexly composed of various structural polymer components such as collagen and hyaluronic acid. Through binding with integrin and CD44, which exist as anchor receptors on the cell surface, ECM is closely connected to the cytoskeletal system and communicates by transmitting mechano-chemical signals.
  • External stimuli cause qualitative and quantitative changes in ECM components. Such changes in the extracellular structural environment lead to changes in the signaling system through mutual mechanical and chemical communication with cells (mechano-chemical crosstalk between ECM and cells), and changes in the original function and homeostasis of the cells, resulting in disease.
Structuring of ECM
Mechano-chemical Crosstalk between ECM and Cells

Reference. J. Glaucoma. Biology of the Extracellular Matrix: An Overview (2015)

SCIENCE

HAPLN1
Confirmation of skin rejuvenation (regeneration of dermal tissue) and related marker changes in the skin
of old mice paired with young mice in the parabiosis mice model through blood exchange
Experimental model for parabiosis between young and old mice

Establishment of a blood exchange system between old and young mice (Heterochronic parabiosis)

Confirmation of blood exchange by parabiosis
Flow cytometry plots depicting GFP (Green fluorescent protein) expression by PBMC (peripheral blood mononuclear cells) isolated from old mice (A), young GFP-Transgenic (Tg) mice (B), old mice joined with young GFP-Tg mice (C) and young GFP-Tg mice joined with old mice (D)
Changes in the skin of parabiosis mice

Confirmation of the tissue regeneration in the dermis of the old mice paired with young mice

As a result of analyzing blood proteins of each blood of paired parabionts, we discovered HAPLN1,
an extracellular matrix protein that may play a critical role in the skin rejuvenation observed in old mice
paired with young mice

Analysis Method: Through aptamer-based proteomic analysis enabling to perform ultra-trace level qualitative
and quantitative analysis of protein groups distributed in the blood, specific cells, tissues, and organs in the body

What is HAPLN1?

HAPLN1 (Hyaluronan And Proteoglycan Link proteiN1) is an endogenous glycoprotein widely present in the extracellular matrix (ECM) of human and animal blood or tissues that stably binds hyaluronic acid (high molecular polysaccharide) and proteoglycan (complex glycoprotein) stoichiometrically. It exhibits various effects and functions such as moisturizing, viscosity, elasticity, etc. As a mechanical, chemical, and biological defense material against external stimuli, HAPLN1 has a characteristic that decreases with aging.

HaplnScience, Inc. is the first in the world to discover a new function of HAPLN1 that not only rejuvenates aging skin but also promotes regeneration of various human tissues that are deteriorated with age by identifying HAPLN1 as an endogenous protein that rejuvenates the dermis of old mice, through an experimental heterochronic parabiosis study.

When the purified recombinant HAPLN1 was administered to old mice, the epidermal and dermal layer thickness increased, and collagen and hyaluronic acid levels, which were significantly reduced compared to the young mice, were restored. Interestingly, in the established alopecia model using mouse, it was observed hair generation was remarkably promoted in a beta-catenin-dependent manner.

In addition, when recombinant HAPLN1 was administered to the knee joint cavity of a mouse osteoarthritis model, the levels of collagen 2 and aggrecan, which are the biomarkers of cartilage regenerative capacity, were significantly increased. Similar efficacy and pain relief effect were also observed in rat and goat osteoarthritis models,

demonstrating the possibility of its development as a candidate for First-in-Class DMOAD (Disease-Modifying Osteoarthritis Drug). On the other hand, in the elastase-induced mouse model of Chronic Obstructive Pulmonary Disease (COPD), which occurs frequently in the elderly due to smoking and fine dust, when recombinant HAPLN1 was inhaled in the form of an aerosol, it was observed that the alveolar walls, which were already destroyed/damaged due to disease induction, recovered to the almost normal level. It showed its potential as a drug candidate for a fundamental, regenerative treatment against emphysema in COPD, which has not yet been developed over the world. HaplnScience aims to develop a first-in-class protein drug that can fundamentally treat various refractory chronic diseases caused by aging-related degeneration while clarifying the mechanism of action that explains these new functions of the recombinant HAPLN1.