In recent years, the approval of nucleic acid therapeutics for listing has been accelerating. Numerous nucleic acid therapeutics that have the potential to become blockbuster drugs have released clinical data covering cardiovascular and metabolic diseases, liver diseases, and a variety of rare diseases. Especially after the approval of the two mRNA COVID-19 vaccines, nucleic acid therapeutics have received more and more attention from the world.

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Nucleic Acid Therapeutics: Recent Development
In recent years, the approval of nucleic acid therapeutics for listing has been accelerating.
Numerous nucleic acid therapeutics that have the potential to become blockbuster drugs
have released clinical data covering cardiovascular and metabolic diseases, liver
diseases, and a variety of rare diseases. Especially after the approval of the two mRNA
COVID-19 vaccines, nucleic acid therapeutics have received more and more attention
from the world.
Nucleic acid therapeutics have obvious advantages. Traditional small-molecule
chemicals and antibody drugs mostly work by binding to target proteins, but their
development is limited by the druggable properties of target proteins. According to Nature
reports, of the ~20,000 proteins encoded by the human genome, only 3,000 are druggable,
and only 700 corresponding drugs have been developed. Meanwhile, antibody drugs
usually only target cell membranes and extracellular proteins. Nucleic acid therapeutics
can regulate genes expressing related proteins based on the principle of base
complementation, such as ASO, siRNA, miRNA, saRNA, etc., instead of binding to target
proteins. Therefore, nucleic acid therapeutics can avoid the limitation of undruggable
targets faced by traditional small molecule chemicals and antibody drugs. At the same
time, the basis of most nucleic acid therapeutics is the principle of base complementary
pairing. As long as the base sequence of the target gene is known, the sequence design
of nucleic acid drugs is very easy, and the design of chemical modification and delivery

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system and sequence design is relatively independent. In contrast, in the discovery and
optimization of small molecule and antibody drugs, the optimization of properties such as
activity and PKPD requires structural changes, which requires a lot of work.
The development process of nucleic acid drugs has not been smooth. Exogenous
nucleic acid drugs need to overcome multiple obstacles to enter the body:
 1) It is unstable and easily degraded by nucleases in the body;
 2) Nucleic acid molecules are immunogenic and will activate the response of the
human immune system;
 3) The molecular structure is large and negatively charged, which makes it difficult
to penetrate the cell membrane;
 4) After entering the cell, the nucleic acid molecule needs to escape from the
endosome to the cytoplasm (endosome escape).
In view of the limitations encountered in the delivery of nucleic acid drugs in vivo, various
measures have been applied to try to solve the above-mentioned problems, such as
the chemical modification of nucleotides and the application of delivery systems. Chemical
modification of nucleotides can improve the stability of nucleic acid molecules and reduce
their immunogenicity, including chemical modification of ribose, phosphate backbone,
bases, and nucleic acid chain ends. The development of delivery system technology has
made it possible to prevent nucleic acid drugs from being degraded by nucleases while
improving the efficiency of their entry into cells, such as polymers, lipids (liposomes or
LNP), GalNAc, peptides, antibodies, etc.
The research and development of nucleic acid drugs are divided into a variety of technical
routes, including ASO, siRNA, Aptamer, miRNA, mRNA, saRNA, sgRNA, U1 snRNA, etc.

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 1) ASO is a single-stranded structure, chemical modification can effectively
improve its stability, immunogenicity, half-life and other properties. Moreover, it is an
amphiphilic molecule (hydrophilic and lipophilic), which is relatively less dependent on the
delivery system, and can be administered in the form of naked nucleic acid. Curently,
there are 7 ASOs are approved by FDA and EMA.
 2) siRNA is one of the current research hotspots of nucleic acid drugs. It induces
gene silencing through RISC, and the development of delivery system technology has
greatly promoted the development of siRNA drugs. At present, 4 siRNA drugs have been
approved by the FDA & EMA, and many siRNA drugs that are expected to become
blockbuster drugs have published clinical data.
 3) Due to the COVID-19 epidemic, the research and development of mRNA
vaccines have received more attention and great progress has been made. Two mRNA
vaccines have been granted EUA by the FDA. LNP technology is applied in these two
vaccines as a delivery system, consisting of a neutral phospholipid, cholesterol,
a polyethylene-glycol (PEG)-lipid, and an ionizable cationic lipid, among them, PEG can
enhance the stability and lifespan of LNPs. At the same time, protein replacement
therapy based on the mRNA route is also being explored.
In addition, the research and development of Aptamer, miRNA, saRNA, sgRNA, U1
snRNA and other types of nucleic acid drugs are all proceeding quickly.
Product Gene target Indication Administration Approval year
ASOs
Vitravene, fomivirsen (Ionis
Pharmaceuticals)
Cytomegalovirus gene (UL123) Cytomegalovirus infection Intravitreal
1998 (withdrawn
2002/2006)
ondys 51, eteplirsen (Sarepta
Therapeutics)
Dystrophin (exon 51) Duchenne muscular dystrophy Intrathecal 2016
Tegsedi, inotersen (Ionis
Pharmaceuticals)
Transthyretin (TTR) TTR-mediated amyloidosis Subcutaneous 2018
Spinraza, nusinersen (Ionis
Pharmaceuticals)
Survival of motor neuron 2
(SMN2)
Spinal muscular atrophy Intrathecal 2016

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Kynamro, mipomersen (Ionis
Pharmaceuticals)
Apolipoprotein B-100 Hypercholesterolemia Subcutaneous 2013
Waylivra, Volanesoren (Ionis
Pharmaceuticals / Akcea)
Apolipoprotein CIII Familial chylomicronemia syndrome Subcutaneous 2019
Vyondys 53, golodirsen
(Sarepta Therapeutics)
Dystrophin (exon 53) Duchenne muscular dystrophy Subcutaneous
2019 (confirmatory tria
required)
Amondys 45, casimersen
(Sarepta Therapeutics)
Dystrophin (exon 45) Duchenne muscular dystrophy Subcutaneous 2021
GalNAc−siRNA conjugates
Givlaari, Givosiran (Alnylam
Pharmaceuticals)
ALAS1 Acute hepatic porphyrias Subcutaneous 2019
Leqvio, inclisiran
(Novartis/Alnylam
Pharmaceuticals)
PCSK9 Hypercholesterolemia Subcutaneous 2020
Oxlumo, lumasiran (Alnylam
Pharmaceuticals)
Glycolate oxidase Primary hyperoxaluria type 1 Subcutaneous 2020
LNP-RNA
Onpattro, patisiran (Alnylam
Pharmaceuticals)
TTR siRNA TTR-mediated amyloidosis Intravenous 2018
Comirnaty, tozinameran
(BioNTech/Pfizer)
SARS-CoV-2 spike protein
mRNA
COVID-19 (FDA, emergency use;
Switzerland, full approval)
Intramuscular 2020
mRNA-1273
(Moderna/NIAID/BARDA)
SARS-CoV-2 spike protein
mRNA
COVID-19 (FDA, emergency use) Intramuscular 2020
AAV vectors
Glybera, alipogene tiparvovec
(uniQure)
Lipoprotein lipase (LPL) (AAV1) LPL deficiency Intramuscular 2012 (withdrawn 2017)
Luxturna, voretigene
neparvovec-rzyl (Spark
Therapeutics)
RPE65 (AAV2) Leber congenital amaurosis Subretinal 2017
Zolgensma, onasemnogene
beparvovec (AveXis/Novartis)
SMN1 (AAV9) Spinal muscular atrophy Intravenous 2019
Adenovirus (Ad) vectors
axzevria, AZD1222, ChAdOx1
nCoV-19 (AstraZeneca)
SARS-CoV-2 spike protein DNA
(ChAdOx1)
COVID-19 (FDA and EMA emergency
use)
Intramuscular 2021
Ad26.COV2.S (Johnson &
Johnson)
SARS-CoV-2 spike protein DNA
(Ad26)
COVID-19 (FDA and EMA emergency
use)
Intramuscular 2021

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Convidecia, Ad5-nCoV
(CanSinoBIO)
SARS-CoV-2 spike protein DNA
(Ad5)
COVID-19 (Approved in China) Intramuscular 2021
Nucleic acid therapeutics approved by the FDA and EMA. Source: Reference [1]
With the advancement of clinical practice and the maturity of related technologies, the
approval of nucleic acid drugs has accelerated significantly in recent years. At present,
many different kinds of nucleic acid drugs are entering or have been in different clinical
stages, and their indications are becoming more extensive and even curing some
diseases. It is expected that as more difficulties are overcome, more nucleic acid drugs
will be clinically applied. Nucleic acid drugs are expected to become the third-largest type
of drugs after small molecule chemicals and antibody drugs.
As a global partner, Biochempeg can supply commercial quantities of high-quality
functionalized PEGs, which are essential for your PEGylated nucleic acid
therapeutics. We will PEGylate your nucleic acid therapeutics and deliver your
PEGylated product with a certificate of analysis, as a regular end-product, for further
testing at your site.
References:
[1] Kulkarni, J.A., Witzigmann, D., Thomson, S.B. et al. The current landscape of nucleic
acid therapeutics. Nat. Nanotechnol. 16, 630–643
(2021). https://doi.org/10.1038/s41565-021-00898-0
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