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Next Generation Immunology & Gene Therapy Breakthrough: Small Nucleic Acid Drugs

Release time:

2019-05-17 18:16

From1998First antisense nucleic acid drug inFomivirsenSo far, it has been listed.8A small nucleic acid drug was approved.2018Year8Month10Day, by the United StatesAlnylamDeveloped by pharmaceutical companiesCorns(Patisiran) announced the acquisition of U. S.FDAapproved for use by hereditary transthyretin amyloidosis (hATTR) peripheral nerve disease (polyneuropathy, polyneuropathy, FAP) Adult patients,FAPfor the rareTTRGenetic diseases caused by genetic mutations,TTRGene mutations can cause abnormal amyloid deposition in the liver, which can damage body organs and tissues including peripheral nerves and heart, and induce diseases such as peripheral sensory neuropathy, autonomic neuropathy, and cardiomyopathy, which seriously affect the quality of life and are fatal. High, this disease is difficult to control with traditional drugs, andRNADrug searchPatisiranIt can be selectively degraded.TTRofmRNAAvoid the synthesis of toxic proteins. This isFDAFirst ApprovedRNAInterference (SiRNA) mechanism drugs, alsoFDAThe first approved for the treatmenthATTRtherapy of patients with polyneuropathy caused.

 

mechanism of action of small nucleic acid drugs

As we all know, organismsDNAThe information on the gene fragment is mainly through the messenger.RNA(mRNA) to protein, whileRNAInterference (RNA interference, RNAi) is the unique gene silencing mechanism of eukaryotic cells to resist the invasion of foreign substances, protect the stability of genetic information, and regulate various functions of organisms.

RNAInterference (RNA interference, RNAi) refers to the long chain doubleRNA(Double-stranded RNA, dsRNA) Induced homologymRNAthe phenomenon of efficient and specific degradation,DsRNAis cut20-25 bpThe small interferenceRNA(Narrow interfering RNA, siRNA,), loadSiRNAInduced interference complex (siRNA induced interference complex, RISC),RISCand then the complementary target genemRNAbinding in the form of base pairing, inducingmRNAIt degrades and ultimately silences specific gene expression.

Based onRNAiVarious techniques established/Drug applications are often referred to as small nucleic acid technology/drugs, small nucleic acids including mediatedRNAiThe short double strandRNAFragment (SiRNA）、MiRNAand antisense nucleic acids, etc., which are based onSiRNADrugs are currently the most concerned.

Traditional small molecule drugs and protein drug targets are mostly proteins, including kinases, receptors, antigens, etc., but many diseases are caused by gene mutations that cause problems with the corresponding proteins.RNAiThe discovery has greatly broadened the source and development direction of human drugs, expanding drug targets to the upstream of proteins-RNAIt enables small nucleic acid drugs to be treated at the post-transcriptional level, with the advantages of short pre-clinical development cycle, rich candidate targets, high specificity, high efficiency and long-term efficacy.

The indications of small nucleic acid drugs cover a wide range, including tumors, rare diseases (amyotrophic lateral sclerosis, Duchenne muscular dystrophy, spinal muscular atrophy), viral diseases, cardiovascular diseases (insufficient coagulation, dyslipidemia, etc.), inflammatory diseases (asthma, arthritis, colitis), etc., but rare diseases and tumors are the most widely used areas.

 

The main pioneer of small nucleic acid pharmaceutical in China

In China, Suzhou Ruibo Biotechnology Co., Ltd. is committed to developingRNAInnovative drugs that interfere with technology.2017Year12In January, Suzhou Rebo and its strategic partner, the United States.QuarkPharmaceutical companies (Quark Pharmaceuticals, Inc.) Development of small nucleic acid drugsQPI-1007Completed the first clinical administration in China, small nucleic acid drugsQPI-1007It is intended for the treatment of non-arteritic anterior ischemic optic neuropathy (NAION), and has the potential to treat glaucoma at the same time;2017Year4In January, Suzhou Rebo announced a relationship with the nucleic acid pharmaceutical giant.IonisSigning a cooperation agreement, obtainingIonisThree separate treatments for metabolic diseases and cancerRNAAll R & D and commercialization rights of targeted drugs in China.

At present, Suzhou Ruibo has applied for a number of domestic and foreign invention patents, the relevant patent situation is summarized in the table below. WithSiRNAWith the establishment of the platform and technology, the company has gradually established a rich product pipeline, including for hepatitis B, hyperlipidemia and other indications.SiRNATherapy.

Open No.

Patent Name

Application Date

Legal status

CN101820921B

Inhibition of tyrosinase gene expressionSiRNAand compositions and applications

2008-08-26

Authorization

CN101889087B

Composite molecule for interfering with expression of target gene and preparation method thereof

2008-11-28

Authorization

EP2233573B1

A complex molecule interfering the expression of target genes and its preparing methods

2008-11-28

Authorization

CN101921745B

MATPGene interference target site sequence and small interference nucleic acid and composition and application.

2009-06-11

Authorization

CN101921744B

PGene interference target site sequence and small interference nucleic acid and composition and application.

2009-06-11

Authorization

CN102083983B

Small nucleic acid interference target site sequence and small interference nucleic acid of hepatitis B virus gene, composition and application

2009-08-03

Authorization

CN101868473B

Preparation method of oligonucleotide

2009-09-22

Authorization

US8569476

Method for preparing oligonucleotide

2009-09-22

Authorization

EP2380896B1

Method for preparing oligonucleotide

2009-09-22

Authorization

JP5253578B2

Methods of synthesis of oligonucleotides

2009-09-22

Authorization

CN102028947B

FAM3BInhibitors and compositions of genes and methods of inhibition, as well as therapies and pharmaceutical uses of inhibitors of fatty liver.

2009-09-29

Authorization

US8754058

Inhibitors of FAM3B gene, inhibitor compositions, inhibiting methods and applications of inhibitors in preparing pharmaceuticals

2010-11-26

Authorization

CN102140460B

Small interference nucleic acid and pharmaceutical composition and pharmaceutical application thereof

2010-01-29

Authorization

CN102140461B

Small interference nucleic acid and pharmaceutical composition and pharmaceutical application thereof

2010-01-29

Authorization

CN102140459B

Small interference nucleic acid and pharmaceutical composition and pharmaceutical application thereof

2010-01-29

Authorization

CN102140458B

Small interference nucleic acid and pharmaceutical composition and pharmaceutical application thereof

2010-01-29

Authorization

CN102337263B

inhibition of enterovirus71type of gene expressionSiRNAand compositions and applications

2010-07-21

Authorization

CN102344477B

a nucleotide and/or oligonucleotide and preparation method thereof

2010-07-27

Authorization

US9567364

Nucleotide and/or oligonucleotide and preparation process thereof

2011-07-20

Authorization

EP2599784B1

Nucleotide and/or oligonucleotide and preparation process thereof

2011-07-20

Authorization

JP5728086B2

Nucleotides and/Or oligonucleotides and their synthesis methods

2011-07-20

Authorization

CN102727907B

a small interferenceRNADrug delivery systems and formulations

2011-04-13

Authorization

CN102827225B

a nucleotide and/or oligonucleotide and preparation method thereof

2011-06-14

Authorization

CN103987846B

Double-stranded nucleic acid and application and kit thereof in ribonuclease detection

2012-09-10

Authorization

US9540682

Double-stranded nucleic acid, use and kit thereof in ribonuclease detection

2012-09-10

Authorization

CN104024413B

Small interferenceRNAand its application and inhibitionplk1Methods of Gene Expression

2012-10-19

Authorization

CN106467915A

Small interferenceRNAand its application and inhibitionplk1Methods of Gene Expression

2012-10-19

Substantive review

US9328348

Small interference RNAs, uses thereof and method for inhibiting the expression of plk1 gene

2012-10-19

Authorization

US9593335

Small interference RNAs, uses thereof and method for inhibiting the expression of PLK1 gene

2016-04-15

Authorization

CN105473164A

Nucleic acid and pharmaceutical composition and application thereof

2014-08-26

Substantive review

CN106467565A

Deoxyribose oligonucleotide and preparation method thereof

2016-03-02

Withdrawal after publication

CN107849567A

a kindSiRNA, containingSiRNAPharmaceutical compositions and conjugates and their applications.

2016-06-24

Substantive review

CN108431224A

Small interference nucleic acid and pharmaceutical composition and use thereof

2016-08-31

Substantive review

CN108220293A

Small interference nucleic acid and pharmaceutical composition and use thereof

2016-12-21

Substantive review

CN108210510A

Small interference nucleic acid pharmaceutical composition and use thereof

2016-12-21

Substantive review

CN108239643A

inhibition in humans and animalsTIMP-1gene expressionSiRNA, compositions containing them and applications thereof

2016-12-23

Substantive review

CN108239644A

Small interference nucleic acid and pharmaceutical composition and use thereof

2016-12-23

Substantive review

CN108251420A

inhibition in humans and animalsCTGFgene expressionSiRNA, compositions containing them and applications thereof

2016-12-28

Substantive review

CN108251421A

inhibition in humans and animalsCOL1A1gene expressionSiRNA, compositions containing them and applications thereof

2016-12-28

Substantive review

CN108265052A

Small interference nucleic acid and pharmaceutical composition and use thereof

2016-12-30

Substantive review

 

Summary

The development of disruptive technologies such as small nucleic acid drugs is destined to be ups and downs, but with the unremitting efforts of generations, small nucleic acid technology is also making breakthroughs. The obstacle of small nucleic acid drug technology is not selectivity, but stability, immunogenicity, large-scale production and other traditional drugs are rarely encountered difficulties. Whether small nucleic acid drugs can break through their own limitations and become a new biopharmaceutical industry direction after antibody drugs still needs to be broken through in key technical links such as drug delivery and large-scale synthesis.

 

References:http://med.sina.com/article_detail_103_2_56987.html

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