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Eli Lilly and gene-editing company Precision BioSciences recently entered into a potential $2.7 billion partnership to open the pipeline for gene therapy for Duchenne muscular dystrophy (DMD), becoming one of the few pharmaceutical companies studying the field。
Duchenne muscular dystrophy (DMD) is an X-chromosome linked recessive genetic disease caused by anti-muscular dystrophy protein (Dys) gene mutation, which leads to progressive muscle damage and motor function decline throughout the body。According to relevant statistics, the incidence of DMD in male infants is about 1/6000-1/3500, and the overall prevalence is about 15/100,000-20/100000。Typically, by the age of 4, patients will have abnormal walking, slow movement, unable to stand steadily and other symptoms, by the age of 12 need to rely on equipment to travel, and eventually by the age of 20 due to respiratory and heart failure leading to death。
However, until now, there is no clinical treatment for DMD that can cure this disease。
Glucocorticoids, as the traditional treatment for DMD, can delay the progression of the disease, but there are serious adverse reactions。Exon jumping therapy is also used to treat some DMD patients，At present, two drugs of Sarepta Therapeutics have been approved by the FDA in 2016 and 2019，Eteplirsen(Exondys 51) and Golodirse(Vyondys 53).。Exon-hopping drugs targeting exons 45/51/53 are also being developed。However, the treatment also has technical difficulties with low delivery efficiency, and the half-life is relatively short, requiring patients to receive intramuscular injections every two weeks。
With the continuous development of gene therapy, new discoveries have been made for DMD, among which the use of gene editing to treat DMD can directly remove the mutated exon. The biggest advantage of this therapy is that it can truly cure patients without repeated medication。In addition, gene therapy mediated by AAV virus is also included, but the length of the anti-muscular dystrophin gene is about 2600kb, which is far more than the load of AAV virus and is difficult to introduce into the body to play a role。Therefore, partial truncated anti-muscular dystrophin genes that are still functional can be loaded into some AAV virus vectors with good affinity to muscle cells, so as to achieve the purpose of cure。However, this method is currently difficult to establish durable protein expression。
In fact, before Lilly, Pfizer was one of the first pharmaceutical giants to deploy DMD, as early as 2016, Pfizer acquired gene editing company Bamboo Therapeutics for DMD drug development。But it wasn't until May of this year that Pfizer's research and development process took off。In addition, Sarepta Therapeutics is also working on a gene therapy for DMD, SRP-9001, which is also making good progress。
According to the Grand View Research report, the global market size of DMD drugs is expected to reach 41 percent in 2023.$100 million and will be paid with 41.Growth at a compound annual rate of 3%。
Now, with Lilly's heavy participation, it may bring a new turning point for DMD treatment。
The following is the relevant research progress in this paper。
1, Lilly and Precision BioSciences
近日，Lilly and Precision BioSciences have entered into a partnership agreement，The two parties agreed to use Precision's ARCUS genome editing platform to research and develop therapies for potential genetic diseases，Lilly has the right to select three genetic targets，Including DMD related research。During the partnership, Precision will lead preclinical research and support activities related to an investigational New Drug Application (IND), while Lilly will be responsible for the clinical development and commercialization process。
ARCUS is a highly specific and versatile genome editing technology platform discovered and developed by Precision that uses a specific sequence of DNA-cutting enzymes or nucleases designed to insert (knock in), remove (knock out), or repair the DNA of living cells and organisms。Among them, I-CreI is a naturally occurring genome editing enzyme，This enzyme is a homing endonuclease，It is mainly found in Chlamydomonas rheinensis，It is possible to make highly specific cuts to cellular DNA，To correct the problem of genetic defects at the source，At the same time, self-inactivation after editing，To avoid editing non-target sites。
To date, ARCUS has shown potential through animal models to treat genetic disorders other than DMD, including autosomal dominant retinitis pigmentosa (adRP), familial hypercholesterolemia (FH), and hereditary thyroxin-carrying protein amyloidosis (ATTR).。The ARCUS approach to DMD is to restore the expression of dystrophin by deleting exon 45-55。
For Lilly, this collaboration is focused on Precision's ARCUS technology, in addition to gene editing technology is emerging as a promising therapy for genetic diseases that currently have no effective treatment, and Lilly can use the platform to create drugs with translational potential。
2Pfizer and Bamboo Therapeutics
2020In November, Pfizer announced that its investigational gene therapy candidate PF-06939926, which is being developed to treat DMD, has received fast track status from the US FDA。
This designation is based on the latest data from the Phase Ib study of PF-06939926。Preliminary data from 9 ambulostatic DMD boys showed that intravenous infusion of PF-06939926 had a good safety profile and sustained anti-muscular dystrophin expression levels for 12 months。
PF-06939926It is a Phase Ib multi-center, open-label, non-randomized, escalating dose study initiated by Pfizer in 2018。The purpose of this study was to evaluate the safety and tolerability of this investigational gene therapy。PF-06939926 uses the AAV9 vector to carry a truncated or shortened version of the human dystrophin gene, which is controlled by a human muscle-specific promoter。AAV9 capsid has the potential to target muscle tissue and is a relatively suitable vector。
3Sarepta and Roche
Sarepta TherapeuticsIt is a leader in precision genetic medicine for rare diseases, and current gene therapies for DMD include SRP-9001。In September 2020, Sarepta announced the results of the SRP-9001 study。Results from a 2-year follow-up of four ambulate patients (4-7 years of age) showed that NSAA assessments continued to improve from baseline on average 2 years after a one-time SRP-9001 injection。SRP-9001 was well tolerated by all patients over a 2-year period。
SRP-9001The aim is to deliver the gene encoding microdystrophin to muscle tissue so that muscle cells express microdystrophin。The advantage is that SRP-9001 has the potential to deliver therapeutic benefits regardless of where in the Dystrophin gene a DMD patient has the mutation。In December 2019, Roche and Sarepta signed a 28-year agreement.A $500 million license agreement gives exclusive rights to SRP-9001 outside the United States。Sarepta is responsible for the global development and manufacturing of SRP-9001 and plans to commercialize SRP-9001 in the United States。
2020In July, SRP-9001 was granted fast-track status by the US FDA for the treatment of DMD。In addition, SRP-9001 has been granted rare pediatric disease status by the FDA。SRP-9001 has also been granted orphan drug status in the United States, the European Union and Japan。
Although no gene therapy products have been approved in the field of DMD, the results of ongoing studies by Pfizer and Sarepta and Roche suggest that gene therapy is still worth looking forward to。
(Source: Shell Society)） | 
