Introduction, types and drug delivery of RNA based therapeutic drugs.

1. Shri Balasaheb Mane Shikshan Prasarak Mandal Ambap’s
ASHOKRAO MANE COLLEGE OF PHARMACY,PETH VADGAON
DEPARTMENT OF PHARMACEUTICS
TITLE OF SEMINAR:- "RNA-Based Therapeutics: A Paradigm
Shift in Drug Discovery and Delivery
SEMESTER -I
Academic Year 2023-24
Miss. Swapnali. S. Gadade.
Presented by
Miss. Swapnali Siddheshwar Gadade.
M. Pharm First Year
Department of Pharmaceutics. First Year
Department of Pharmaceutics.ar
Department of Pharmaceutics.
Guided by
Dr. Sachin .S. Mali
Professor and Head,
Department of pharmaceutics.

2. Content
 Introduction
 Types of RNA Therapeutic
 Historical overview of RNA therapy
 Drug Discovery of RNA therapy
 Drug Delivery of RNA therapy
 Literature review
 Future prospective
 Conclusion

3. Introduction
 RNA therapies can manipulate gene expression and produce therapeutic
proteins, these drugs have potential to target established genetic targets,
including infectious diseases, cancer, immune disorders, and Mendelian
disorders (including neurological diseases).
 The realization that thousands of untreatable diseases can now be treated
represents a paradigm shift that opens many opportunities for the use of
nucleoside drugs.
 To overcome obstacles to safe and effective RNA delivery, scientists are
developing viral vector-based vectors that protect RNA from degradation,
maximize delivery to target cells, and minimize exposure to off-target cells.

4. Types of RNA Therapeutics


5. 1.Aptamers:-
 Aptamers are single-stranded oligonucleotides with a well-defined three-
dimensional structure that specifically bind and inhibit proteins.
 They are also called chemical antibodies due to their synthetic origin and
antibody-like mode of action.
 Systematic evolution of ligands by exponential enrichment was used for aptamer
selection.

6. 2.Antisense Oligonucleotide:-
 Antisense oligonucleotides are small DNA or RNA oligonucleotides that can
specifically hybridize to RNA molecules.
 These are synthetic polymers in which some or all of the natural nucleotide
monomers of the oligonucleotide are chemically modified deoxynucleotides (in
DNA) or ribonucleotides (in RNA).
 Antisense technology uses single-stranded DNA or RNA molecules to target
specific sense mRNAs. Antisense oligonucleotides contain 15 to 22 monomers
and are often referred to as "oligos."

7. 3.RNA Interference :-
 RNA interference (RNAi) is an evolutionarily
highly conserved post-transcriptional gene
silencing (PTGS) process.
 As a result, when double-stranded RNA
(dsRNA) is introduced into cells, it triggers
sequence-specific degradation of homogolic
mRNA sequences.
 It was first discovered in the nematode
Caenorhabditis elegans by Andrew Fire and
Craig Mello in 1998, and has since been
discovered in a variety of organisms, including
mammals.

8. 4.mRNA:-
 Another type of RNA therapeutic is mRNA, which can encode proteins with
therapeutic activity. Due to its size, mRNA is transcribed in vitro and cannot
currently be generated using solid-phase synthesis with site-specific chemical
modifications.mRNA can be used to replace proteins, use replacement
therapies to reduce protein levels, use tue cleavage approaches, or use base
editing to repair mutations at the DNA level.

9. Historical overview of RNA therapy

10. Numerous discoveries have established RNA therapy as an indispensable technology for
treating human disease:-
 This discovery formed the basis for the subsequent discovery of microRNAs (miRNAs) in 1993 and RNA
interference in 1998. There, the generation of RNA duplexes is a key step in RNA silencing.
 The discovery of reverse transcriptase in 1970 was therefore important.
 It is used in the production of almost all mRNA-based medicines. Subsequently, Conry et al. developed the
first mRNA vaccine to treat cancer in 1995.
 In the 2000s, the use of RNAi and siRNA to silence human genes was proposed, and funding for RNA
therapeutics increased. Other RNA molecular regulators and associated mechanisms are also well
characterized.
 In the 2020,mRNA-1273 and BNT162b emergency use for SARS-CoV-2 pandemic.
 In the 2022, mRNA-based therapeutics: powerful and versatile tools to combat diseases.

11. RNA therapeutics are a new class of drugs based on ribonucleic acid (RNA)
 The main types of RNA therapy are those based on messenger RNA (mRNA), antisense RNA (asRNA),
RNA interference (RNAi), and RNA aptamers.
 mRNA therapy is particularly useful for vaccine development because it is the only treatment that relies
on triggering protein synthesis within cells. .
 Antisense RNA is complementary to the coding mRNA and is used to trigger inactivation of the mRNA to
prevent it from being used for protein translation.
 RNAi-based systems use both small interfering RNA (siRNA) and microRNA (miRNA). ) to prevent
translation of mRNA and/or mRNA degradation .
 RNA aptamers are short, single-stranded RNA molecules formed through directed evolution that bind to
various biomolecular targets with high affinity and interfere with their normal activity in vivo.

13. Delivery System
 Lipid-Based Drug Delivery
 Nanotechnalogy
 Extracellular Vesicles
 Intracellular Delivery
 Inhalation,intranasal, or injection Delivery
 Chronic dosage
 Tissues Targeting

14. 1.Lipid-Based Drug Delivery :-
Lipid-based drug delivery systems (DDS) for IA administration ,their functions, and
RNA therapeutics, including small molecule disease-modifying anti-osteoarthritis
drugs (DMOADs), and nonsteroidal anti-inflammatory drugs (NSAIDs) Overview of
classes of encapsulated therapeutics and corticosteroids.

15. 2.Nanotechnalogy:-
Nanotechnology has emerged as a promising approach for delivering mRNA
molecules, enabling the development of mRNA-based therapeutics such as
vaccines and gene therapy.
Nanotechnology-based delivery systems such as-
 lipid nanoparticles (LNPs)
 polymeric nanoparticles
 inorganic nanoparticles

16. 3.Extracellular vesicles:-
 Extracellular vesicles (EVs) are small membrane structures secreted into the
extracellular space by various cells.
 They play an important role in intercellular communication, transporting
biomolecules, including proteins, lipids, and nucleic acids, to neighboring or distant
cells.
 In recent years, electric vehicles have emerged as a promising vehicle for mRNA
delivery, providing a new approach for gene therapy and other biomedical
applications.

17. 4.Intracellular delivery:-
 The ability of mRNA therapies to produce high levels of intracellular proteins
compared to protein drugs represents a real added value for these
treatments, and furthermore allows for the rapid production of therapeutic
antibody mixtures.
 There is great potential for intracellular proteins such as: B. Metabolic and
mitochondrial proteins.

18. 5.inhalation, intranasal, or injection Delivery:-
 Unlike the liver, the kidneys act as a filter, excluding large molecules and allowing
only small molecules to pass through.
 When inhaled, the molecules reach the lungs more quickly, allowing the use of
less drug, thereby reducing the severity of unpleasant systemic side effects.

19. 6.Chronic dosage:-
For mRNA to successfully transition from vaccines to therapeutics, it is important
to be able to target and efficiently deliver mRNA multiple times while
maintaining high protein yields. Recombinant protein-based enzyme replacement
therapy strongly illustrates this point.
7.Tissues Targeting:-
• For mRNA therapy to reach its full potential, further improved in vivo delivery
techniques are required. These systems are particularly important for
parenchymal organs such as the heart, kidneys, brain, and lungs.
• In terms of convenience of administration, the liver is the organ of choice for most
molecular drugs. The fenestrated vasculature facilitates effective administration of
homogeneous substances and facilitates the movement of large particles.

20. Application of RNA Therapy

21. Literature Review
1. Andrew Fire and Craig C. Mello et. al(2006) Reviewed about or their
discovery of “RNA interference – gene silencing by double-stranded RNA.”
2. John.c.Burnet and John.J. Rossiet.al(2012) Reviewed about the clinical
results of siRNA, RNA aptamer, and ribozyme therapeutics.
3. Deepiksha Pande et.al(2016) Reviewed about the main scitific and technical
aspects of RNA interference.
4. Kalina Paunovska et. al(2022) Reviewed about the preclinical drug delivery
research to clinical approval.
5. Sarfaraz k. Niazi et.al (2023) Reviewed about COVID-19 brought about the
mRNA vaccine and a paradigm shift to a new mode of treating and preventing
diseases

22. Future Prospects
 Although clinical trial barriers must be overcome for RNA-based therapeutics
to be successful in the future, results from studies to date offer important
lessons.
 In general, siRNA requires some chemical modifications to minimize
nonspecific inflammation, while natural or synthetic carriers should be used
for efficient and tissue-specific delivery.
 Similar to siRNA, ribozymes and aptamers face similar delivery and off-target
toxicity challenges.
 These RNA drugs can be chemically modified and, depending on the
application, can also be delivered through gene therapy.
 Overall, these and other examples of RNA-based therapeutics have shown
promise in the treatment of cancer, viral, and genetic diseases.

23. Conclusion
 Significant advances have been made in RNA-based therapeutics in recent
years, with some products entering clinical trials.
 Currently, RNA-based therapeutics are primarily used as reagents for
research and drug development. Future possibilities lie in clinical applications.
 Specific complementary base pairing, specific catalytic properties, the ability to
sense microenvironmental signals, and the ability to adopt distinct secondary
structures to modulate gene expression make RNA-based therapeutics
specific and effective.
 The main obstacles are the targeted delivery of these molecules to cells and
theis stability in serum. However, with the advent of nanoparticle
applications in drug targeting, these problems may be resolved.
 RNA-based therapeutics interact with technologies such as drug delivery and
molecular diagnostics and play a role in the development of personalized
medicine.

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