These trends were identified by analyzing 149 clinical trials of AAV gene therapy...

AAV is a single-stranded DNA virus, and the current scientific consensus is that it does not cause any human disease, consisting of a capside and a single-stranded DNA genome of 4.7kb in length.
end reverse repeat sequence (inverted terminal repeat, ITR) at both ends of the AAV genome, which is the starting point for virus DNA replication and the signal that triggers virus packaging.
recombinative adeno-related viruses (rAAAVs) used in gene therapy vectors carry almost identical protein shells to wild AAVs, but the part of the genome that encodes viral proteins is completely replaced by therapeutic transgene.
149 unique clinical trials, 94 of which have been completed and 51 have reached the end of the treatment.
the number of trials launched each year increased from 5 in 2010 to 26 in 2017.
most of the studies that reached the end point were Phase 1/2 clinical trials, with an endpoint of safety and efficacy.
, more than 80% of the research was supported by industry bidders.
duration of the study showed a trend of shortening overall.
, about 10 different serotonype AAVs are used as vectors for gene therapy in clinical trials.
analysis showed that AAV2 serotypes remained the most used serotypes throughout the study period and had the most evidence of safety and ability to be validated in more than 40 completed clinical trials.
since 2015, the number of drug trials using AAV8 and AAV9 casings delivered to the central nervous system (CNS) has been increasing, reflecting an increase in the use of gene therapy in CNS disease.
new wardrobes such as AAV-LK03, SPK-100 and AAV-HSC15 are being looked at, but they show limited evidence of safety and effectiveness.
common starters CBA, CAG and CMV are still the three most commonly used starters, as they have been shown to work well in previous studies and are suitable for a wide range of systems.
between 2015 and 2019, one of the three initiaters was used in 45 percent of trials that disclosed startup information.
In addition to universal starters, three new trends have emerged in recent years: first, tissue-specific strong initiaters have been used in more than 25 clinical trials, such as albumin and synactin, to achieve tissue-specific expression of the gene of the purpose.
, the modification of gene box design and the improvement of the ability to produce larger doses of AAV make it possible to use natural promoters of inserted genes in gene therapy.
third, synthetic initiaters targeting specific cell subse groups have been successful in animal studies, although the efficacy of such initiaters has not been proven in clinical trials.
in terms of safety, the analysis covered 3,328 patients who received the trial treatment, 9 of which were considered to be 4/5 severe adverse events (TESAEs) in treatment, but were not directly attributable to the death of patients with GM or clothing.
no studies were terminated for safety reasons before the deadline for this paper, and all completed studies reached their safety endpoints (n-51).
However, reports after the paper's deadline showed that 3 out of 17 patients receiving higher doses of experimental gene therapy AT132 for X-series muscular dystrophy died from aggressive liver and bile disease, as well as subsequent sepsis and gastrointestinal bleeding.
in terms of efficacy, most of the 94 completed trials available for analysis were on four organs: the eye, liver, muscles and central nervous system.
gene therapy, which targets the liver, has been shown to address both metabolic and blood conditions.
, as well as haemophilia A and haemophilia B, are the three most clinical trials.
of drug success rates is inevitably limited by the small number of drugs.
based on 11 drugs that have reached the stage of new drug application (NDA), the chance of progressing from experimental new drug (IND) application to NDA is 36%, and the medium duration from IND to NDA is 86 months.
the highest overall probability of success in hematology gene therapy (from IND to NDA of 56%).
the end of this article, the authors conclude, based on clinical data covering more than 20 years and 3,000 patients, that AAV gene therapy is a safe, well-to-withstand and effective treatment;
, the durability of gene therapy is uncertain due to a lack of lifetime follow-up.
, improvements in manufacturing processes have led to an increase in the average dose of AAVs used in clinical trials, which may eventually cause side effects in the liver or other organs.
, with the exception of the eyes, liver, muscles and central nervous system, major organs such as the heart, kidneys and lungs still have little access to AAV gene therapy.
gene therapy is an innovative treatment that has received industry attention.
and as a powerful means of delivering GM, the research and development of AAV carrier platform is also growing exponentially.
we look forward to overcoming the challenges we face today and realizing the full potential of AAV gene therapy as the field of AAV research and development continues to expand and multidisciplinary tools are applied.
: s1, C., Samulski, R.J. Engineering adeno-associated virus vectors gene for therapy. Nat Rev Genet 21, 255–272 (2020).[2] Dmitry A. Kuzmin et al., The clinical landscape for AAV gene therapies. Nature Reviews Drug DiscoveryI.