What is periodontitis?
Periodontitis is a chronic inflammatory condition caused by dental plaque that damages the supporting tissues around the teeth.
It is among the most common oral diseases and is the leading cause of tooth loosening in adults, often resulting in both functional impairment and aesthetic concerns – affecting oral health and overall quality of life.
It’s the 6th most prevalent health condition worldwide, and beyond its impact on oral health, periodontitis is strongly linked to an increased risk of various systemic diseases.
Periodontitis is classified into stages from initial to severe, reflecting how much damage has occurred. Your periodontist may also assign a grade, which indicates how quickly the disease is progressing and how it may respond to treatment – with aggressive periodontitis having a high rate of progression.
How it affects the patient
- Red, swollen, or bleeding gums, bad breath, and gums that pull away from teeth leading to deep pockets.
- Daily quality of life is affected, as the effects of periodontitis can make eating, speaking, and smiling painful and challenging.
- In severe cases, without proper care, periodontitis can destroy the gums and bones supporting your teeth, ultimately causing permanent tooth loss.
Current Treatments
- First-line: professional deep cleaning (scaling and root planning).
- Selected cases: local or systemic antimicrobials or adjunctive drugs.
- Advanced cases: periodontal surgery and grafting.
- Long-term maintenance and good home care are essential to preserve results and prevent relapse.
However, these treatments only manage progression of the disease, requiring lifelong maintenance to prevent recurrence.
No effective medical treatment exists that combines both antibacterial and anti-inflammatory properties, which both are crucial for effectively combating periodontitis.
Maintaining oral health
is essential for quality of life
and can contribute to
reducing the risk of systemic
health issues.
Disease Prevalence
- Periodontal diseases affect 20-50% of the global population – making it the 6th most prevalent health condition.
- Severe periodontitis affects 11% globally
- Over 50% of the European population suffer from some form of periodontitis and over 10% have severe disease, with prevalence increasing to 70-85% of the population aged 60-65 years of age
- In the U.S. 42% of people aged 30+ are affected by periodontitis.
- 7.8% of the U.S. population has advanced periodontitis.
Severe Periodontal Disease – Key Facts
- Primarily affects middle-aged and older adults.
- Peak incidence: around age 60.
- Global Burden of Disease (2019):
- Disability-adjusted life years (DALYs) from oral disease increased 75% (1999–2019).
- Severe periodontitis is a major contributor compared with dental caries.
- Prevalence by age group:
- Only 1.7% of younger populations affected.
- Sharp increase after age 30–40.
- Highest prevalence: ages 65–74.
- European data: prevalence significantly higher in adults 65–74 vs. 35–44.
Economics
Scientific rationale for the effect of LL-37
LL-37 is the active ingredient in our drug candidate and has the following key advantages:
- It possesses both antibacterial and anti-inflammatory properties.
- It is an endogenous molecule, naturally produced within the body
- It has potential bone regenerative capabilities, a particularly exciting finding since periodontitis erodes the bone structure supporting the teeth.
Research has shown that periodontitis patients have lower levels of LL-37 in their bodies, reinforcing its potential as an ideal active ingredient for a periodontitis drug.
LL-37 is the only known human cathelicidin antimicrobial peptide
- Produced mainly by neutrophils, epithelial cells, and macrophages
- Functions:
- Directly kills bacteria, fungi, and some viruses
- Neutralizes bacterial endotoxins (like LPS)
- Modulates inflammation and wound healing
- Attracts immune cells (chemotactic role)
LL-37 in Periodontitis
Periodontitis is driven by a dysbiotic biofilm and a destructive host immune response. LL-37 plays a double-edged role:
- Protective Effects
- Found in gingival crevicular fluid (GCF) and saliva.
- Is key to regulating inflammation to prevent excessive tissue damage.
- Acts against periodontopathogens such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, etc. Porphyromonas gingivalis, Fusobacterium nucleatum
- Supports wound repair of gingival tissues
- Membrane disruption:
- LL-37 is cationic (positively charged) and amphipathic
- It binds to negatively charged bacterial membranes, inserts itself, and forms pores or micelle-like disruptions
- This leads to leakage of cell contents → bacterial death
- Effective against Gram-positive, Gram-negative bacteria, fungi, and some viruses
- Can also bind and neutralize bacterial endotoxins (LPS) to prevent septic inflammation.
Wound Healing & Tissue Regeneration
- Stimulates angiogenesis (via VEGF induction)
- Promotes fibroblast and keratinocyte migration/ proliferation
- Speeds up closure of epithelial wounds
- Deficiency and Susceptibility
- Genetic deficiency (e.g., in Papillon–Lefèvre syndrome, caused by cathepsin C mutations) leads to very low LL-37 and aggressive periodontitis at an early age
- Reduced LL-37 levels in GCF are associated with higher periodontal pocket depth and attachment loss
Anti-Biofilm Activity
- Inhibits microbial biofilm formation (important in periodontitis and chronic infections)
- Disrupts established biofilms, making bacteria more sensitive to immune attacks or antibiotics.
Deficiency → Aggressive Disease
- Patients develop severe early-onset periodontitis due to impaired neutrophil antimicrobial function
- Suggests LL-37 is essential for periodontal defense.
Immune Modulation
- Chemotaxis:
- Attracts immune cells (neutrophils, monocytes, mast cells, T cells) via formyl peptide receptor-like 1 (FPRL1)
- Cytokinemodulation:
- Can also suppress overactive inflammation by neutralizing LPS and dampening Toll-like receptor (TLR) signaling
- Acts like a “tuner” of inflammation → boosts defense but prevents tissue damage
- Consequences:
- Attracts neutrophils and other immune cells → amplifies local inflammation
- Elevated cytokine release (IL-1β, TNF-α, IL-8) → connective tissue and bone destruction
- Thus, LL-37 can contribute to collateral tissue injury if not properly regulated.
Diagnostic / Clinical Relevance
LL-37 is a key innate immune molecule in the periodontium. Adequate levels are protective against pathogens, but deficiency predisposes to severe periodontitis, while dysregulated overexpression may contribute to tissue destruction.
- Produced mainly by neutrophils, epithelial cells, and macrophages
- Prevents biofilm formation and neutralizes LPS, reducing bacterial virulence
- Helps maintain host–microbe balance in the oral cavity
- Biomarker: LL-37 levels in saliva or GCF could be explored as a diagnostic or prognostic marker of periodontal disease activity
- Therapeutics: Synthetic LL-37 or analogs might be used as adjunctive antimicrobial/host-modulatory therapies, but dosing must be controlled to avoid exacerbating inflammation.
- Potential therapeutic strategies:
- Normal levels: Antimicrobial, healing, balanced immune response
- Deficiency: Infections (e.g., aggressive periodontitis, skin infections)
- Excess: Chronic inflammation (psoriasis, rosacea, arthritis)
- Synthetic LL-37 peptides or analogs to boost deficient defense
- Modulation of LL-37 expression to balance antimicrobial effect vs. tissue inflammation
- Protective when present in normal amounts (antimicrobial, immune balancing, wound healing)
- Harmful when deficient (susceptibility to aggressive disease) or when excessive (excess inflammation and tissue breakdown).