What are the medical applications of polynucleotides?

Medical Applications of Polynucleotides

Polynucleotides have emerged as versatile therapeutic agents with applications in RNA interference, mRNA vaccines, gene therapy, and skin rejuvenation, with lipid nanoparticle delivery systems showing the most clinical success for systemic applications.

Types of Therapeutic Polynucleotides

Polynucleotides used in medical applications can be categorized into several major groups:

1. RNA Interference (RNAi) Therapeutics

• Small Interfering RNAs (siRNAs):
  • 20-25 nucleotide-long double-stranded RNA molecules that direct RNA-induced silencing complex (RISC) to cleave target RNA 1
  • Examples of approved therapies:
    • Onpattro (patisiran) - First FDA-approved RNAi drug using lipid nanoparticle delivery for hereditary transthyretin-mediated amyloidosis 1
    • Givlaari (givosiran) and Oxlumo (lumasiran) - GalNAc-conjugated siRNAs 1

2. Antisense Oligonucleotides (ASOs)

• 15-20 nucleotide-long single-stranded DNA oligomers that bind to complementary RNA and induce cleavage by ribonuclease H 1
• Clinical applications include:
  • GSK3228836 - Shows significant reduction in hepatitis B surface antigen (HBsAg) in clinical trials 1

3. mRNA Vaccines

• Utilize lipid nanoparticle delivery systems similar to Onpattro
• Notable examples:
  • COVID-19 vaccines by BioNTech/Pfizer (Comirnaty) and Moderna (mRNA-1273) 1
  • Applications expanding to viral infections and cancer vaccines 1

4. DNA Vaccines

• Plasmid DNA encoding antigens for immune response stimulation
• Can induce both cell-mediated and humoral immune responses 2
• Can be modulated by co-administration of plasmid-encoded cytokines 2

5. Dermal Rejuvenation Polynucleotides

• Polynucleotides Highly Purified Technology (PN-HPT™) for skin rejuvenation and revitalization 3
• Used for face, periocular area, neck, hands, scalp, and stretch marks 3

Delivery Systems for Polynucleotides

The effectiveness of polynucleotide therapeutics heavily depends on their delivery systems:

1. Lipid Nanoparticles (LNPs)

• Most successful delivery system for systemic applications 1
• Components include:
  • PEGylated lipids to prevent immune clearance
  • Cationic ionizable lipids for RNA encapsulation and endosomal escape
  • Cholesterol and structural lipids 1
• Used in Onpattro and COVID-19 mRNA vaccines 1

2. Conjugation Systems

• GalNAc (N-acetylgalactosamine) conjugation:
  • Allows efficient liver-targeted delivery via binding to asialoglycoprotein receptors on hepatocytes
  • Requires extensive chemical modifications to protect RNA from degradation 1
• PEGylation: Improves stability and pharmacokinetics 1

3. Viral Vectors

• Adeno-associated viral vectors (AAVs)
• Challenge: Immune response against viral components can limit repeated dosing 1

Clinical Applications by Therapeutic Area

1. Infectious Diseases

• COVID-19 vaccines: mRNA vaccines encoding SARS-CoV-2 spike protein 1
• Hepatitis B: siRNAs and ASOs targeting HBV components:
  • JNJ-3989: Induced HBsAg decrease >1.0 log10 IU/mL in 98% of participants 1
  • AB-729: Similar reduction in HBsAg titer 1
  • GSK3228836: Mean reduction >1.5 log10 IU/mL in serum HBsAg titer 1

2. Genetic Disorders

• Hereditary transthyretin-mediated amyloidosis: Treated with Onpattro (patisiran) 1

3. Cancer Immunotherapy

• CAR-T cell therapy: CRISPR-Cas gene editing for creating chimeric antigen receptor T cells 1
• Cancer vaccines: mRNA encoding tumor antigens 1

4. Dermatology and Aesthetics

• Skin rejuvenation: PN-HPT™ for biostimulatory boosting and revitalization 3
• Protocols available for face, periocular area, décolleté, neck, hands, scalp, and stretch marks 3

Challenges and Considerations

1. Delivery Challenges

• Nuclease degradation in bloodstream
• Cellular uptake and endosomal escape
• Tissue targeting specificity 1

2. Safety Concerns

• Off-target effects: Risk of affecting unintended genes or pathways 1
• Delivery vehicle toxicity: Potential immunogenicity of lipid components 1
• Post-treatment reactivation: In viral treatments, risk of reactivation by remaining viral components 1
• ALT flares: Need for monitoring during treatment 1

3. Regulatory Considerations

• Regulations for mRNA therapeutics are evolving
• Current regulations for preclinical biodistribution data are described as "vague and ill-defined" 1
• Classification discrepancies: mRNA vaccines against infectious diseases are not considered gene therapeutics by FDA/EMA, while mRNA vaccines against cancer are classified as gene therapy products 1

Future Directions

• Development of more specific targeting strategies
• Improved delivery systems with reduced toxicity
• Expansion of applications to other disease areas
• More robust regulatory frameworks as the number of RNA therapeutics increases 1

The field of polynucleotide therapeutics is rapidly evolving, with lipid nanoparticle delivery systems showing the most clinical success for systemic applications, while direct injection approaches are proving effective for localized treatments like skin rejuvenation.