Adeno-associated virus as a delivery vector for gene therapy of human diseases
Oldest Genetic Disorder Few Kenyans Know About - The Standard
Haemophilia Comprehensive Care Clinic will be opened at the Coast General Hospital to mark the triumphs of persons with Haemophilia. (Photo: Maarufu Mohamed, Standard)Today, Kenya joins the globe in celebrating the triumphs of persons with a bleeding disorder known as Haemophilia.
From writings of rabbinical readings, haemophilia existed as early as the 2nd century, AD, in the laws and traditions that gave reprieve for baby boys from being circumcised especially if their two older brothers died during the rite of passage.
This year the event in Kenya will be marked in Mombasa to mark the opening of the Haemophilia Comprehensive Care Clinic at the Coast General Hospital, bringing the number of specialist haemophilia clinic to three after Kenyatta National Hospital and Moi Teaching and Referral Hospital in Eldoret.
This year's theme, 'lighting it up red' seeks to increase visibility by creating awareness about this condition that impairs the body's ability to make blood clots, a process needed to stop bleeding.
Haematologist Kibet Shikuku estimates there are more than 4,300 people with haemophilia in Kenya. However, only 600 haemophilia patients have been diagnosed and registered to attend a specialised comprehensive care clinic for the condition.
Collaborative approach
Dr Shikuku, hailed the new centre specialised to take care of haemophilia patients in the Coastal region, adding it will require a multi-sectoral collaborative approach of medicine to efficiently treat and manage haemophilia.
"This is a milestone in the development and strengthening of healthcare services for haemophilia patients in Kenya while lifting the financial, emotional and psychological burden associated with haemophilia to both patients and parents," said Dr Shikuku.
Witty facts on haemophilia
Haemophilia and the symptoms
Haemophilia is a group of inherited blood disorders where the blood does not clot properly.
It was initially referred to as a royal disease because Queen Victoria, Queen of England from 1837 to 1901, was a carrier. Her eighth child, Leopold, had the disease and suffered from frequent bleeds. The disease was also recorded in the Spanish, German and Russian Royal families.
An individual suffering from the disease lacks a protein called a clotting factor, which works with platelets to stop bleeding at the site of an injury.
In case of an injury, the person bleeds spontaneously or longer in case of surgery.
This happens because of a defect in one of the clotting factor genes on the X chromosome.
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Acquired and inherited haemophilia
Acquired haemophilia affects both women as well as men, can occur at any age although it is more common in adults.
It occurs when the immune system recognises the body's own factor eight as a foreign protein and thus makes an antibody to destroy it. This antibody is also known as an inhibitor because it inhibits its work.
Expected signs and symptoms
Some of the most prevalent signs and symptoms include excessive bleeding and easy bruising. The bleeding can occur internally or externally.
Excessive internal bleeding is evident when there is blood in the urine or stools and presence of large, deep bruises. Bleeding can also happen within joints, like knees and elbows, causing them to become swollen, hot to touch, and painful to move.
Bleeding in the brain is evident in case the person experiences persistent headaches, vomiting, behavioural changes, clumsiness, eye problems, paralysis, and seizures.
Men and haemophilia
Being a sex-linked disorder, it is more common in males than females. Females have XX sex chromosomes while males have XY sex chromosomes. Males lack a second X chromosome to make up for the defective gene. Females are carriers of haemophilia, but they are unlikely to have the disorder. For a girl to have haemophilia, she must have the abnormal gene on both of her X chromosomes, a rare occurrence. For a female carrier, there are four possible outcomes for each pregnancy:
1. A girl who is not a carrier
2. A girl who is a carrier
3. A boy without haemophilia
4. A boy with haemophilia
Operating haemophiliacs and replacement therapy
The basic treatment to stop or prevent bleeding in people with haemophilia A and B is factor replacement therapy. Replacement therapy can be a form of treatment for bleeds or a preventive measure. The concentrates come from two sources:
1. Human plasma (a component of blood) or
2. A genetically engineered cell line made by DNA technology, called recombinant.
Minor injuries like bruises do not need replacement therapy.
Prevalence of Haemophilia
Globally, one in every 5,000 males is haemophiliac.
In Kenya, there are 450 people diagnosed with haemophilia out of an estimated 4,000 men. About 3,600 people remain undiagnosed with haemophilia alone.
Haemophilia A and B
The diagnosis for this disease is determined through a blood test.
Hemophilia A, also known as classic hemophilia is associated with X-chromosome, which prominently afflicts males. It is due to the deficiency or complete absence of factor VIII in the blood. Women are mostly carriers of this condition, and transmit the condition to male children.
Hemophilia B is the second most common kind of bleeding disorder, also termed as factor IX deficiency. The disease is prominently genetic, although in 30 per cent of cases, the condition has been reported without any family history of the disease. It is caused by deficiency or absence of clotting factor IX.
Initiation rites, circumcision of haemophiliacs
Families face anxiety and social stigma if one of them has this bleeding disease and cannot undergo the cultural rite of passage, circumcision.
Circumcision is a minor surgery that has few complications. However in persons with haemophilia, the spontaneous and prolonged bleeding can lead to death if undisclosed.
Low self-esteem and haemophilia
Young men with haemophilia may develop low self-esteem that can trigger suicidal tendencies if they do not participate in play to avoid injuries that lead to bleeds.
Support groups for haemophiliacs play a great role in psychological support for both the patience, their parents, guardians and family members because they share experiences thus strengthening their resolve to deal with this condition.
Inhibitors effects on treatment
Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working. They make the replacement therapy less effective and this could cause severe complications for the patient.
Haemophilia patients who develop inhibitors are twice as likely to be hospitalised to deal with complications of the disease.
A lab test is necessary to establish whether a person with haemophilia has developed inhibitors.
Arthritis and joint pains
The disease causes crippling joint pain. The most commonly affected muscles are those of the arms and leg.
Haemophilia can lead to hemarthropathies - bleeding into the joint space of a joint which causes stiffness and pain. The blood also causes scars inside the joint and hardening of the joint space, making the pain more pronounced.
However it is difficult for doctors to distinguish between joint pain caused by arthritis and that caused by bleeds by haemophilia.
Sources: World Health Organisation, www.Haemophilia.Org, World Federation of Haemophilia and Kenya Haemophilia Association.
The writer is a Health and Medicine Editor at The Conversation Africa
What Is Hemophilia A? And More FAQs - Medical News Today
Many people with hemophilia A can lead ordinary, active lives. Learning more about this genetic condition can support effective long-term management strategies.
Hemophilia A is a genetic condition that is present from birth. It can be inherited or de novo (caused by a genetic change that occurs during embryonic development). Like other types of hemophilia, hemophilia A prevents proper blood clotting.
This article explores the frequently asked questions about hemophilia A, including its causes, severity, and impact on quality of life.
Hemophilia A is one of two primary types of hemophilia — the other is hemophilia B. Hemophilia A is a genetic condition that prevents the body from making enough of clotting factor VIII (factor 8). Clotting factors are proteins in the blood that are involved in coagulation (clot formation).
Clots are part of the body's healing process. They control blood loss and create a matrix that supports tissue repair.
People with hemophilia A have a genetic change on the F8 gene of their X chromosome that affects the production of clotting factor VIII. Without enough clotting factor VIII, coagulation is interrupted. As a result, clots may not form, may form slowly, or may not be stable if they do form.
Hemophilia A varies in severity, depending on how the F8 gene is altered. Genetic changes can result in a mild, moderate, or severe deficiency of clotting factor VIII. The lower the level of clotting factor VIII, the more serious the bleeding can be.
Mild hemophilia A, which involves clotting factor VIII levels of 6% to 40%, rarely causes spontaneous bleeding (episodes of internal hemorrhaging that result from an unknown cause or from everyday activities). Though it is considered mild, this type of hemophilia A will still result in prolonged or excessive bleeding as a result of minor tissue trauma.
Bleeding episodes are more common in severe hemophilia A. With clotting factor VIII levels of less than 1%, severe hemophilia A may periodically cause spontaneous bleeding.
The life span for someone with hemophilia A varies depending on the severity of the condition and on individual factors such as age, co-occurring conditions, and medical management.
Research suggests that hemophilia has an association with a lower life expectancy overall. In a 2020 study involving more than 1,000 men in the Netherlands, researchers found that the median life expectancy for those with hemophilia was 77 years — 6 years lower than the median for the larger population of men.
In a 2023 study in the United States, researchers found that between 1999 and 2020, the median life expectancy for males with hemophilia increased from 54.5 to 65.5 years. However, racial disparities were significant, with a 12-year difference in the median age at end of life between non-Hispanic Black males (56 years) and non-Hispanic white males (68 years).
Quality of life (QoL) is a measurement of how well a person feels. In hemophilia A, QoL varies depending on the severity of the condition and individual variables such as overall health, lifestyle habits, and treatment adherence.
A 2019 survey found that health-related QoL among people with severe hemophilia A was low. The most common challenges that survey participants cited were pain, anxiety, depression, and physical limitations due to joint pain.
QoL in milder forms of hemophilia A may be higher. With treatment and safety measures, many people can maintain ordinary levels of activity and function.
Hemophilia A primarily affects males due to inheritance patterns. The condition appears on the X chromosome.
In females, two X chromosomes are present (XX), one from the father and one from the mother. Males have one X chromosome from their mother and a Y chromosome from their father (XY).
In females, an unaffected X chromosome can compensate for the F8 genetic change on the other X chromosome. However, because males have only one X chromosome, the altered F8 gene will affect the production of clotting factor VIII.
Females can still have factor VIII deficiency if the second X chromosome is not working or if both X chromosomes have the genetic change, but males are more likely to experience severe bleeding.
This means females with an F8 genetic change are less likely to have significant symptoms, while all males with an F8 change for hemophilia A will have clotting factor VIII deficiency.
Clotting factor VIII deficiency in hemophilia A does not worsen with age. If a person does not receive treatment for the condition, the severity that is present at birth will remain consistent throughout the person's life.
However, hemophilia A symptoms may become more noticeable as a result of natural age-related changes in the body, illness, chronic injury, or co-occurring medical conditions. Over time, spontaneous bleeds can cause long-term damage to some areas of the body, such as the joints.
Hemophilia A affects the body's ability to form blood clots. It is a genetic condition caused by a change in the F8 gene on the X chromosome.
With treatment and everyday safety precautions, many people with hemophilia A can lead active, ordinary lives. Quality of life and life expectancy can vary depending on factors such as the condition's severity and a person's age, lifestyle, and co-occurring medical conditions.
Treatment Options For Hemophilia A - Medical News Today
Hemophilia A is a genetic bleeding disorder caused by a deficiency in clotting factor VIII. Treatment focuses on managing bleeding episode symptoms with clotting factor replacement therapy, immunotherapies, and gene therapy.
Hemophilia A results from genetic variations to the F8 gene on a person's X chromosome. The F8 gene directs the production of clotting factor VIII, one of many proteins involved in blood clotting during bleeding.
Without enough factor VIII, blood clotting becomes impaired. Clots may not form quickly enough or provide enough structural stability to support wound closure. Bleeding does not speed up in hemophilia A but can persist for longer.
While there is no cure for hemophilia A, various treatment approaches can help manage it. This article looks at the standard treatments used in hemophilia A as well as emerging and novel therapies.
The first-line approach to treating hemophilia A involves replacing missing factor VIII. It involves supplementing clotting factor VIII from human blood plasma (plasma-derived factor VIIII) or factor VIII made in a laboratory using genetic engineering (recombinant factor VIII).
Plasma-derived factor VIII goes through an extensive purification process to reduce the risk of transmitting infectious agents, but a small risk does remain.
Recombinant factor VIII is considered much safer. It does not contain components of human blood.
Factor VIII replacement therapy involves an intravenous infusion.
Depending on the severity of hemophilia A, a person may receive infusions as needed during a bleeding episode, known as on-demand treatment, or on a regular schedule proactively, known as prophylaxis therapy.
On-demand treatment may also consist of desmopressin. Desmopressin is a synthetic hormone that stimulates the release of factor VIII contained within the structures of blood vessels. Doctors can use it in mild hemophilia to help manage a bleeding episode.
Results from a 2022 cohort study suggest that desmopressin can be effective in controlling minor bleeds, especially when added to factor VIII replacement infusions.
Transfusions of fresh frozen human plasma or whole blood only take place if factor VIII concentrates are not available or there is a need to replace additional blood components.
Antifibrinolytic agents are supplementary medications to prevent blood clots from breaking down. Doctors typically use them during minor surgeries, dental procedures, or traumatic injuries to help with bleeding.
Tranexamic acid and aminocaproic acid are antifibrinolytic agents commonly used in hemophilia A.
Doctors consider genetic therapy and other second-line treatments for hemophilia A when a person develops inhibitors to traditional factor VIII replacement. Inhibitors are antibodies the immune system makes that attack replacement factor VIII as if it were a bacteria or virus.
Gene therapy
In hemophilia A, gene therapy aims to counteract the genetic alteration that causes factor VIII deficiency. Doctors do this by inserting a functional copy of the F8 gene into a person's cells using vectors, small molecules that can deliver genetic material into a cell.
The most common vectors in gene therapy for hemophilia A are called adeno-associated virus (AAV) vectors. They use harmless viral variants as their mode of transport.
Gene therapy works by providing a functional copy of F8, which allows the body to produce its own factor VIII.
In 2023, the Food and Drug Administration (FDA) approved the one-time gene therapy Roctavian (valoctocogene roxaparvovec) for hemophilia A treatment. It uses an AAV vector to transport a functional copy of F8 into a person's liver cells.
A 2024 report on the phase 1 clinical trial results of valoctocogene roxaparvovec reported good safety and efficacy during a 7-year follow-up, with the majority of participants maintaining an adequate level of clotting function from the treatment.
Gene therapy may have more benefits than just providing clotting factor VIII. A 2023 review suggests gene therapy in hemophilia A can help reduce the presence of inhibitors through a process called immune tolerance induction (ITI).
In theory, by allowing the body to make its own controlled amounts of factor VIII with genetic modification, a person's immune system could be trained to become more tolerant of synthetic factor VIII replacement.
Immunotherapies
Immunotherapies are treatments that target, modify, or enhance a person's immune function to help treat hemophilia A.
One current targeted immunotherapy medication in hemophilia A is emicizumab.
Emicizumab is a bispecific monoclonal antibody. It works by mimicking the action of factor VIII, which allows the body's clotting cascade to complete and produce stable clots.
Sometimes, suppressing the immune system can benefit a person with inhibitors. In these circumstances, doctors use immunosuppressive treatments (ISTs). ISTs focus on eliminating inhibitor antibodies that compromise traditional therapies.
Standard medications in ISTS include:
Bypassing agents
Bypassing agents work to improve a person's clotting function by enhancing other pathways involved in the clotting process. As with traditional replacement therapy, doctors can administer them on-demand or as prophylaxis treatment.
Examples of available bypassing agents include:
Hemophilia A is a genetic bleeding disorder caused by a genetic alteration in the F8 gene, which results in clotting factor VIII deficiency. Without enough factor VIII, a person's blood is unable to form stable clots, and bleeding can become prolonged.
Replacement of factor VIII is the mainstay of hemophilia A treatment. Doctors can supplement this with other therapies to support clotting processes and address challenges with the development of antibodies called inhibitors.
Gene therapy, immunotherapy, and bypassing agents are all second-line treatments that can help improve outcomes.
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