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Yesterday, the world's first hemophilia B gene therapy Hemgenix (etranacogene
dezaparvovec) received FDA approval
.
Hemgenix is owned by CSL
Behring developed a gene expressing the coagulation factor IX.
(FIX) Padua variant using an adeno-associated virus 5 (AAV5) vector
.
According to the FDA press release, this is the first gene therapy
approved by the FDA for the treatment of moderate to severe hemophilia B.
.
This good news comes as we note that the field of gene therapy has grown
by leaps and bounds in the past decade with the approval of multiple gene therapies.
So what's next, what gene therapies will also benefit patients? What is the current development of gene therapy? In this article, WuXi AppTec's content team combed through the global gene therapy pipeline panorama to see what progress is being made
globally at present and in the future.
in global gene therapy are taking place.
Note: The gene therapies discussed in this article correct or compensate for diseases caused by defective and abnormal genes by introducing functional genes, including in vivo gene therapy (direct delivery of therapeutic genes to the patient's patient site) and in vitro gene therapy (special cells such as stem cells are genetically engineered and transplanted into the human body), excluding oligonucleotides, CAR-T and other therapies
.
List of gene therapies on the market
List of gene therapies on the marketAccording to public information, as of November 9 this year, a total of 10 gene therapies have been approved in the United States, the European Union and Japan (see above for the definition of gene therapy).
In 2012, Glybera was approved, the first adeno-associated virus (AAV) vector-based gene therapy for the treatment of lipoproteinase deficiency; In 2017, Luxturna was approved in the United States, the first in vivo gene therapy approved by the FDA for the treatment of hereditary retinal dystrophy
.
Since then, approved gene therapies have gradually emerged, mainly in the field of
rare diseases.
Compared with the initial frequency of approval of one gene therapy of several years, the frequency of gene therapy approval has accelerated
significantly in recent years.
Regulators predict that the pace of gene therapy approvals will continue to accelerate
in the future.
The U.
S.
FDA expects it to approve 10-20 cell and gene therapies per year by 2025
.
significantly in recent years.
Regulators predict that the pace of gene therapy approvals will continue to accelerate
in the future.
The U.
S.
FDA expects it to approve 10-20 cell and gene therapies per year by 2025
.
▲The first batch of gene therapies in the United States, the European Union and Japan (data cut-off: November 9, 2022; Image source: WuXi AppTec content team mapping) Note: This figure only includes the first approval of gene therapy, and the marketing of the same therapy in other regions is not included in this figure
.
▲The first gene therapy disease coverage in the United States, the European Union and Japan (data cut-off date: November 9, 2022; Image source: WuXi AppTec content team mapping) Note: This figure only includes the first approval of gene therapy, and the marketing of the same therapy in other regions is not included in this figure
.
Global clinical gene therapy panorama
Global clinical gene therapy panoramaBy sorting out the global gene therapy clinical pipeline, it is found that as of November 9, 2022, a total of 253 therapies have entered the clinical stage worldwide, including 27 therapies in clinical phase 3, 148 therapies in clinical phase 2 (phase 1/2 classified into phase 2), and 53 therapies in clinical phase 1 (the remaining therapies have not disclosed clinical stage or have been approved).
。 Companies with more clinical-stage gene therapies include Genethon, AGTC, and Orchard
Therapeutics, Sarepta Therapeutics, etc.
, these companies have 5 or more gene therapies in the clinical stage
.
, these companies have 5 or more gene therapies in the clinical stage
.
▲Panorama of gene therapies under development in clinical stages around the world (Image source: WuXi AppTec content team map, only some therapies are shown in the figure)
▲Panorama of gene therapies under development in clinical stages around the world (Image source: WuXi AppTec content team map, only some therapies are shown in the figure)Gene therapy technology milestones
Gene therapy technology milestonesThe development of gene therapy technology can be divided into two stages, the foundation period of basic technology before 2010 and the rapid development period
after 2012.
After the concept of gene therapy was proposed in 1972, how to deliver genes across the body's various natural barriers to specific sites, and how to integrate genes into the body's own genome
, seemed difficult.
Therefore, gene editing tools and delivery tools are crucial
in the development of therapeutic technologies.
In 1984, adeno-associated virus (AAV) vectors, which are essential for gene therapy in vivo, were developed
.
However, due to safety incidents in the field of gene therapy, therapy development has entered a period of
stagnation.
In 1996, the first generation of gene editing technology ZFN was discovered, and gene editing technology was still in a slow development stage
.
after 2012.
It wasn't until 2012 that the discovery of a new gene-editing tool, CRISPR, brought a new technological milestone
to gene therapy.
The development of CRISPR technology has made gene editing simple and efficient, leading gene therapy into a period
of rapid development.
However, CRISPR technology still has certain limitations, traditional CRISPR technology can not efficiently insert long chain fragments in the genome or directionally change a nucleotide.
Base editing technology is designed to precisely change a single letter in a patient's genome, representing companies including Beam
Therapeutics and Verve Therapeutics
.
Among them, Verve
Therapeutics treated the first patient with cardiovascular disease with a single-base editor in July, an important step
forward in the use of gene-editing technology to treat common diseases.
Other novel gene-editing technologies such as Prime
Medicine's prime editing technology and Tessera Therapeutics' gene writing
writing) technology, which aims to modify DNA sequences more flexibly and precisely, or write large pieces of DNA into the genome
.
to gene therapy.
It is worth noting that despite the rapid progress of gene editing technology, its safety is still an important reference factor
when regulatory approval.
In its guidance on gene editing, released by the FDA in March, it was mentioned that "while the potential of such products in treating diseases is clear, the potential risks are not well understood.
"
Modifications to gene vectors have also been underway
.
On the basis of AAV, scientists modified the prepared recombinant adeno-associated virus (rAAV) to further avoid the risk of gene integration, so it has become an effective carrier
of gene therapy.
However, AAV has a limitation on the size of the delivery gene, and its delivery gene needs to be 4.
7
KB or less
.
To address this challenge, new carrier technologies are constantly evolving
.
.
Non-viral vectors avoid limitations
in gene delivery size.
Among them, lipid nanoparticle (LNP) carrier technology has attracted much attention
with the successful application in mRNA vaccines.
The LNP drug delivery system is a complex structure composed of multiple lipid molecules that encapsulate the drug molecule to avoid immune system attack or nuclease degradation
.
But targeting specific tissues and cells delivered to the human body is the next challenge
in this area.
Most intravenous LNPs accumulate in the liver, and LNPs are not yet able to specifically deliver drugs to most tissues
elsewhere in the body.
New technologies currently under development attempt to incorporate lipids with different biochemical profiles into LNP formulations to improve the efficiency
of delivery to specific target organs.
▲Global gene therapy technology milestones (Image source: WuXi AppTec content team mapping)
▲Global gene therapy technology milestones (Image source: WuXi AppTec content team mapping)Gene therapy is expected to usher in a number of positive developments in the next 1 year
Gene therapy is expected to usher in a number of positive developments in the next 1 yearAccording to incomplete statistics of public information, a number of therapies will usher in positive clinical progress in the next 1 year, including Lumevoq and Lovotibeglogene
Autotemcel and CTX001 are expected to usher in good news for listing or pre-market regulatory submissions, and the rest of the positive developments are shown in the figure below
.
▲Positive progress of global gene therapy in the next 1 year (Image source: WuXi AppTec content team mapping)
▲Positive progress of global gene therapy in the next 1 year (Image source: WuXi AppTec content team mapping)As a unique treatment that promises a "one-time cure", gene therapy has attracted widespread attention
since its inception.
In the ups and downs, gene therapy has gone through half a century, and it is only in the last decade that it has ushered in its rapid development period
.
We hope that more gene therapies can be launched as soon as possible, bringing hope for a cure to patients, and more patients will be free from pain in the future
.
