From repeated bleeding in joints to riding a horse, Chinese hemophilia patients have realized their dreams of grasslands due to gene therapy

From repeated bleeding to riding a beloved steed

"When I was a child, I accidentally got bitten by a mule, but I didn't expect to bleed continuously, and sometimes I could bleed
when I slept in bed.
At that time, the joints hurt so much that I couldn't move, and it was difficult to
walk.
Mr.
Mu Ge recalled that he was diagnosed with severe hemophilia B when he was 5 years old, and due to the lack of advanced treatment concepts and methods in China at that time, he could only receive long-term replacement treatment with prothrombin complex (PCC) (containing coagulation factors II, VII, IX, X and other plasma proteins, a clinical standard treatment
) when joint bleeding occurred.
This also led to repeated bleeding in his multiple joints progressing to synovitis, and eventually hemophilic arthropathy, making his dream of galloping on the savannah since he was a child more and more out of reach
.

(Ecchymosis on the pawn and instep of the shepherd)

Fortunately, in 2018, Mu Ge was introduced by a patient to enroll in Asia's first clinical trial of liver-targeted adeno-associated virus (AAV) hemophilia B gene therapy conducted by Professor Zhang Lei, Professor Yang Renchi and Professor Xiao Xiao's team of East China University of Science and Technology, and achieved the normal level of plasma coagulation factor IX through a single intravenous injection of an AAV vector carrying the coagulation factor IX highly active mutant (FIX Padua) gene, without any excessive bleeding and no need to enter coagulation factors.
A return to a normal lifestyle and significant mitigation of associated complications does not require frequent venipuncture infusions of factor IX drugs
.

However, the pain and limited mobility caused by hemophilic arthropathy still affect the quality of life
of Muge.
Since total knee replacement is currently the only surgical option that can allow him to return to normal activities, Muge strongly hopes to completely solve the joint pathology and restore joint health
through surgery.

(Deformed right knee joint)

"In fact, total knee replacement is a major surgery
that requires extremely high hemostatic ability.
Although Muge's clotting factors have been restored and many hemophilia patients around the world have received gene therapy, no patient has been able to undergo this surgery
without the protection of clotting factors before this operation.
Professor Zhang Lei said that FIX:C after Muge gene therapy remained within the normal range, but whether in animal models or humans, whether FIX Padua's in vivo hemostatic ability can withstand such a major hemostatic challenge is still unknown
.

In order to realize Mu Ge's wish, the research team formed a multidisciplinary collaborative team including hematology, orthopedics, laboratory and rehabilitation, formulated a total knee replacement surgery plan and precautions for perioperative coagulation management, and under the premise of making sufficient and good plans, the patient successfully underwent total knee replacement surgery in the right knee in May 2022, did not receive any coagulation factor IX concentrate replacement therapy during the perioperative period, and did not have excessive bleeding during and after surgery (intraoperative bleeding of about 150mL)
。

Today, Madrigal is recovering very well, moving freely and life is back on
track.
Recently, he sent the research team a photo of him riding a horse on the prairie, and his smile on horseback was even brighter than the scenery of the prairie, and finally realized his dream
of galloping across the vast prairie.

(Group photo with the medical team of the Institute of Blood Research during gene therapy)

Coagulation recovered well during surgery

In the New England Journal of Medicine, the research team detailed the perioperative coagulation indicators of Mu Ge during total knee replacement surgery, showing that in vivo FIX Padua after gene therapy has a good hemostatic effect during major surgery with high requirements for hemostatic ability, which is related
to the FIX:C level measured by the first-phase method.

His FIX:C, which was 50.
1 IU/dL before surgery on the day of surgery, decreased to 46 IU/dL postoperatively, recovered to 53.
8 IU/dL on the first postoperative day, maintained an upward trend until the fifth postoperative day (peak 79.
3 IU/dL) and gradually decreased and stabilized (approximately 60 IU/dL).

Other coagulation factor activity returns to baseline after a mild postoperative decrease
.
Similar trends
are observed in the detection of prothrombin time (PT) and activated partial thromboplastin time (APTT).
Elevation of fibrinogen and D-dimer is a normal postoperative response
.
The Bethesda method did not detect FIX inhibitor production
.

(Partial thromboplastin time (APTT) activated using Dade Actin FSL, FIX activity levels measured using the first-phase method, and perioperative detection of FIX inhibitors)

(Activity of other coagulation factors (coagulation factors II, V, VII, VIII, X, XI and XII)

Professor Zhang Lei said that the research team made sufficient preparations for the operation, assessed the various functions of Mu Ge's body before the operation, formulated a detailed prognosis treatment plan, conducted close bleeding observation after the operation, and helped him carry out rehabilitation training
.
The patient's clotting function and knee function have recovered well
.
However, given that this case is an isolated case, the in vivo hemostatic effect of FIX Padua and its correlation with FIX:C levels need to be further studied
.

(Surgical wound about 15cm long)

Gene therapy for blood disorders is on its way

Hemophilia is a recognized rare disease, and there are about 100,000-120,000 hemophilia patients in
China.
At present, the clinical standard treatment of hemophilia is coagulation factor replacement therapy, although the replacement of the lack of coagulation factors has achieved the purpose of stopping bleeding or preventing bleeding, but patients still need lifelong treatment, bringing heavy economic burden
to patients, families and society.
Therefore, how to cure the disease is the unremitting pursuit of
researchers in the medical community.
At present, gene therapy is the only treatment that is expected to cure hemophilia, and a variety of gene therapy products are still in clinical trials
.

Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), as a national hematology research and diagnosis and treatment platform, has carried out a number of clinical trials to provide more treatment options for hemophilia patients, and a series of original achievements have also enabled China's hemophilia treatment level to stand on the international top stage
.

Among them, the first clinical trial of liver-targeted adeno-associated virus (AAV) hemophilia B gene therapy in Asia, conducted by the team of Professor Zhang Lei, Professor Yang Renchi and Professor Xiao Xiao, confirmed that an intravenous injection of an AAV vector carrying the FIX Padua gene can achieve long-term effective treatment of patients, confirmed the safety and efficacy of liver-targeted AAV vector in Chinese patients, and made the cure of "incurable" hemophilia B from a hope to a reality
。 As one of the subjects of this study, Mu Ge's knee replacement after gene therapy has once again allowed more hemophilia patients to see the hope of a normal life, which is of great significance
to society, family and individuals.

"Hemophilia gene therapy is on the
way.
Our team is not only doing clinical research, but also transforming advanced gene editing and other technologies from basic research to clinical practice, hoping to help more patients with
blood diseases.
At present, there are still many genetic diseases waiting for treatment in China, and it is expected that gene therapy can play a valuable role
in the field of blood diseases and even more diseases in the future.
Professor Zhang Lei said
.

Principal investigator

Typesetting: Guan Yanqing

Editor: Guan Yanqing

Reviewed: Lina Wang

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