What challenges do hemophilia gene therapy need to overcome?

For every serious illness, getting a cure is their ultimate dream! Haemophilia patients are no exception, and when the cascade of blood control was clarified in 1964, there was optimism that the goal of curing haemophilia would be achieved within five years.
many five years have passed, and although the treatment of haemophilia has made great progress, curative therapy has not yet emerged.
however, the 35-year journey to develop a cure for haemophilia is expected to come to an end after successful cloning genes that express coagulation factorviiis VIII (FVIII) and IX (FIX).
BioMarin developed the gene therapy valoctocogene vaparvovec for haemophilia A, which could be approved by the FDA this summer, becoming the first listed gene therapy to treat haemophilia A.
it provides significant protection for some haemophiliacpatients and achieves functional healing effects.
As a new era of hemophilia approaches, Dr. Glenn Pierce, vice president of the World Hemophilia Alliance (WFH), wrote in the journal Haemophilia, reviewing the history of the development of hemophilia gene therapy and describing our attitude towards hemophilia gene therapy.
since being invited to speak to local media about the challenges hemophilia poses, Dr. Pierce has been at the forefront of the fight against haemophilia at the age of 7, and has transformed his role over the past 60 years from a patient suffering from multiple joint bleeding in a wheelchair to being a key leader in the field of haematology in several multinational pharmaceutical companies, driving the birth of five innovative haemophilia therapies.
what makes him even more distinctive is that his haemophilia was cured in 2008 after a liver transplant.
but there is no denying that he remains an important member of the haemophiliac community and has played an absolutely critical role in the organization's humanitarian assistance to developing countries since joining WFH in 2018.
the first wave of haemophilia gene therapy: Experiences and lessons learned from Dr. Theodore Friedmann of the University of California, San Diego, and Dr. Richard Roblin of The Massachusetts General Hospital, who wrote in the 1972 issue of Science that gene therapy could become a powerful tool for treating monogene diseases in humans in the future.
the concept of replacing abnormal genes in the cells of haemophiliacs with normal genes is first seen as a reality as genes encoded FXIII and FIX are cloned.
early basic scientific research using retroviruses to import genetically modified expressions of FXIII and FIX into the body cells of animals and then infuse them into the animals.
although the results of these experiments have been limited, they are sufficient to support the continuation of research in this area.
In 1992, the National Instituteofd (NIH) held its first hemophilia gene therapy summit. Molecular biologists and virologists who develop gene therapy
, and with patient advocates and doctors at haemophilia treatment centers, are working together to explore gene therapies for haemophilia.
as of 2005, a total of five haemophilia gene therapies were in clinical trials.
these clinical trials provide valuable experience and lessons for the development of gene therapy for haemophilia. in a clinical trial at Children's Hospital of Philadelphia and Avigen,
, researchers injected the expression FIX with genetically modified, using adeno-related viral vectors (AAV2) into a patient's liver cells.
this is an important precedent, using intravascular delivery to introduce genetically modified products expressing FIX into naturally produced FIX liver cells.
However, even with the highest dose of gene therapy, the patient's FIX activity reached a maximum of 12% of normal levels during the first 4 weeks of treatment and disappeared completely in the following weeks.
the disappearance of FIX activity was accompanied by a significant increase in liver transaminase levels, which returned to normal after FIX activity returned to the baseline.
this means that all liver cells that can produce FIX are wiped out by the immune system! Subsequent studies found cytotoxic T cells that targeted the specific amino acid sequence of viral shell protein in patients.
this finding led to the termination of the clinical trial and delayed the start of subsequent clinical trials.
subsequent studies have found that the human body's immune response to AAV transfection is a very complex process, and that the difference between the immune response to AAV between humans and animal models, including non-human primates, prevents animal models from effectively predicting the immune response that occurs in human clinical trials.
this is an important lesson learned from clinical trials.
because many people have been infected with AAV, they already have immunity against AAV in their bodies.
this existing immunity includes not only neutralizing antibodies against AAV shell protein, but also memory T cells against AAV.
when AAV vectors carrying gene therapy enter the body, these existing immunitycans can seriously affect the strength and quality of the immune response produced by the body.
in addition, the innate immune response that AAV vector infusion may cause may also promote the production of an immune response to indications.
, therefore, to overcome the human body's immune response to AAV vector needs to consider a number of problems such as serotype, tissue specificity, the quality of the carrier itself and the patient's unique innate immune response.
"multi-pronged approach" to maintain coagulation factor levels based on experience gained in early clinical trials, gene therapy for haemophilia has improved both from the selection of AAV virus vectors, the design of genetically modified organisms, and the treatment process after gene therapy administration.
take valoctocogene roxaparvovec, which is expected to be approved this summer, using the AAV5 virus vector.
AAV5 is unique in that it has the highest homologousity with goats, compared with 65% of the primate AAV shell protein.
because human contact with goats is low, and the cross-reaction of neutralizing antibodies to primate AAV and AAV5 is weak, this means that only a few people in the population carry antibodies that bind to AAV5.
Valoctocogene roxaparvovec also uses hepatocellular-specific promoters, which means that gene therapy does not need to be fed into liver tissue through the liver artery, and only through peripheral venous infusions can still lead to specific expression of coagulation factors in liver tissue.
this can further reduce the potential tissue damage caused by gene therapy administration and the resulting immune response. Genetically modified coders that
express coagulation factors are also optimized to further improve the production of coagulation factors. Professor Amit Nathwani, Professor Edward Tuddenham and their colleagues in clinical trials of gene therapy for hemophilia B,
BioMarin hemophilia A gene therapy (Photo: BioMarin Official Website) pioneered treatment options for the use of corticosteroids to suppress cellular immune response and potentially affect the transfection process.
the program was later applied in clinical trials for haemophilia A.
based on these improvements, a number of current in-therapy treatments for haemophilia have been able to maintain treatment levels of FVIII and FIX over time in clinical trials.
BioMarin has just announced the results of a long-term follow-up of valoctocogene roxaparvovec at this year's World Hemophilia Congress.
four years after receiving gene therapy, the level of FVIII in patients still prevents them from receiving other preventive treatments.
in the treatment of haemophilia B, a mutant called FIX Padua increased the activity of natural FIX by six times due to a mutation in a single amino acid.
this means that a gene therapy dose that could only express 5% normal level OF FIX could increase FIX activity to 30% to 40% of normal levels in clinical trials.
, Pfizer and uniQure are currently in clinical Phase 3 trials for gene therapy for haemophilia B.
uniQure's etranacogene dezaparvovec is expected to obtain Phase 3 clinical trial results by the end of this year.
the company reached a $2 billion research and development partnership with CSL Behring earlier this month.
realize the dream of a cure, but not all patients will benefit from the potential of soon-to-be-approved gene therapy to provide long-term protection for bleeding and even functional cures for some patients.
However, gene therapy using AAV to deliver FVIII or FIX is not perfect and many patients with the disease are not yet able to benefit from it.
for example, haemophilia children who would otherwise benefit from gene therapy are not suitable for gene therapy.
because aAV's genome sexist in the nucleus in the form of an extra-chromosome free gene (episome), they are lost as the cell divides, leading to decreased levels of protein expression.
in young children, the liver grows the fastest, and by the age of 12, their liver is two-thirds the size of an adult.
researchers still need to conduct clinical trials to find out how old a patient is, current gene therapy does not provide long-term protection. The largest group of patients
and unable to receive gene therapy is those who already carry antibodies to AAV.
most of the AAV serotypes currently used in clinical trials come from primates or isolated strains of the virus in humans.
their viral shell homogeneity is about 85%.
there is a cross reaction between different AAV serotypes, which means that patients who have been infected with AAV2 may produce antibodies that cross-react with AAV1, AAV3, AAV6, AAV8, AAV9 and rhAAV10.
if the cross-reaction produces significant antibody titer, then patients cannot accept gene therapy using these AAV serotype deliveries.
currently, most non-primate AAV serotypes, with the exception of AAV5, do not effectively transfect human cells, so high levels of pre-existing immunity are an important barrier that prevents patients from receiving gene therapy or gene therapy for re-administration.
one way to address this barrier is to use different gene therapy delivery systems.
in this regard, the use of slow virus delivery FVIII and FIX gMO has been successful in animal models of non-human primates and dogs.
this technology platform has considerable potential because slow viruses can be integrated into the cellular genome and rarely produce existing immunity in humans.
However, the production of slow virus vectors is still facing challenges, the production of a sufficient number of vectors for clinical trials is currently a problem that research and development personnel need to solve.
embrace the future of gene therapy Over the past 30 years, gene therapy has made significant progress in enabling haemophilia A and haemophilia Patients with near-normal or normal coagulation factor activity.
however, there are still many questions that remain unanswered about its efficacy and safety.
, Dr. Pierce, says embracing gene therapy as a medical model for "cure" haemophilia means pursuing these answers with uncompromising spirit and perseverance while acknowledging the uncertainty surrounding gene therapy.
this will continue to be used in the first generation of haemophilia gene therapy in more patients.
original title: What challenges do hemophilia gene therapy need to overcome to achieve the patient's dream of a cure? Follow the Micro-Wei Public Number of "Drug Mingkang" .