The association for the survivel of Noga Baumatz and others
Noga is a sweet toddler who loves to laugh,cuddle with her mom Tamar and her dad Noam, and play with her sisters Yasmin and Mika.
In the past year, Noga was diagnosed with a rare genetic syndrome called Hoyeraal-Hreidarsson Syndrome (HHS). It causes immune system failure, making the body unfit to cope with infections. The symptoms are many and complex and include Stunt Growth, lung damage, and an inclination to develop cancer and bone marrow failure. This is a progressive disease, meaning it will get worse over time. Noga's life expectancy lies between 3-10 years.
She is now 2.5 years old.
As a result of the weakness of her immune system, Noga suffers from a severe infection in her digestive tract which makes it impossible for her eat or fully digest food. This began when Noga was an infant, so she never learned to eat like other toddlers. Sometimes she wants to eat, but whenever she tries to do it, the food burns her tongue and triggers a vomiting reflex. In order for her to survive, Noga must be connected to a feeding tube 12 hours a day, in a complicated and painful daily procedure.
We were in and out of the hospital for most of the past 2.5 years. Hospitalizations can sometimes last months.
Unlike children her age, Noga is not allowed to roam freely around the playground and discover the world, pet a dog, play with other children or to join her sisters in the swimming pool - because benign infections pose a threat to her life. But even Though she suffers a lot of pain on a daily basis, she remains an incredibly joyful girl. Her smile is infectious, she loves listening to music, playing hide and seek and silly games with her sisters. Her positive attitude keeps us going through the hardest of times.
Keeping the family strong and cohesive under such circumstances is definitely a challenge. Our family life is restricted to the 12 hours a day in which Noga is not connected to an IV, presuming we are not at the hospital with her or having a really rough day. Our older daughters, Yasmin and Mika, are learning to cope with the constant sense of chaos, urgency, and confusion in the house. We rely strongly on the help and support of our family and friends, and on donations we receive.
We were in and out of the hospital for most of the past 2.5 years. Hospitalizations can sometimes last months.
But there is hope,
Gene therapy, the use of normal genes to replace defective or missing ones, has the potential for curing the disease within a single administration. Primary immunodeficiency disorders such as Noga's, are better suited for genetic therapy than almost any other type of genetic disease.
This has already been demonstrated successfully and Highly esteemed doctors and researchers in the field of genetics and immune disease have all agreed that we are on the right track.
In recent years there has been a massive increase in the number of cases treated with genetic therapy, and the pharmaceutical companies are curing genetic diseases that have been considered incurable until now. The problem is that Noga's disease is very rare. there are around 30 known cases worldwide, so no company has the economic incentive to develop a drug.
It is estimated that in ten years, these diseases would become a thing of the past, but Noga doesn't have that time.
We decided we were not going to wait.
After our hope to find an existing cure for Noga shattered, we decided to take matters in our own hands. We began to research all we could find about the syndrome, read everything we could lay our hands on and talked to every expert who was willing to return our calls. Things started to come together.
In recent months we set up our independently financed research team compiled of well-known geneticists, scientists, and doctors from Israel and the world. These experts are dedicated to finding the right genetic treatment customized to treat and heal Noga's syndrome. We rented a lab in September 2018 and started working on development.
If we raise the needed resources, we can save our daughter's life. But we believe that this way of ours will produce something greater, for many other children who suffer from incurable genetic diseases and currently have no treatment options.
Time is a huge factor. Noga is about to enter the more dangerous phase of the disease. We are hoping to identify the exact gene treatment and administer it to Noga within a year. However, laboratory hours, researchers's wages, equipment, and materials are very costly. According to careful estimations, we will need around 500,000 dollars to fund the project which may save our daughter's life. It is a tremendous amount, but it's the only chance we have.
We will be more than grateful for every donation you can make to help Noga survive.
What is Gene Therapy?
Gene therapy is a promising 30-year-old treatment option for genetic disorders, which were generally considered untreatable until recently. While some are hereditary and some are caused by new mutations in the DNA, most genetic disorders are rare, with a prevalence of fewer than 200,000 cases. However, the 7,000 rare diseases combined, affect more than 300 million people worldwide.
Genetic disorders are the outcome of abnormalities in the DNA. The DNA provides the code for making proteins, so any mutation in the DNA affects the protein it codes for, which ceases to function properly. The body’s systems rely on the normal functioning of certain proteins, so the end result of a mutation in the DNA can be a serious impairment in the functioning of systems such as the immune system, the digestive system, the respiratory system etc... “Bubble boy” disease, cystic fibrosis, and several types of vision loss are examples of genetic disorders.
The method of gene therapy consists of replacing defective or missing genes in the cells of people suffering from genetic disorders with normal genes. As opposed to other forms of treatments, gene therapy goes further than just treating the symptoms of the disorder. It targets the abnormal gene, which in-turn treats the underlying cause of the disorder. Also, because gene therapy targets only the abnormal gene(s), it usually has fewer side effects than regular drugs or other forms of treatment. Furthermore, usually one administration will suffice to treat the problem and help the person afflicted with the rare syndrome lead a full and independent life. Gene therapy has the potential for being the closest researchers will ever get to achieving cure for rare disorders, that currently have very limited or no treatment options.
How does gene therapy work?
There are several ways to correct the abnormal genes. In some cases, it will suffice to insert a normal DNA sequence into the nucleus of the cell for the cell to regain its ability to function properly. In more complex cases, the DNA sequence has to be integrated into a chromosome in the cell. If the treatment is successful, the new gene delivered to the cell will start making a functioning protein. The generation of a functional protein from the therapeutic gene restores the target cell to its healthy condition.
One of the best ways to deliver the therapeutic gene into the targeted cells in the body is the use of engineered viruses. A virus makes more viruses by injecting its genetic material into the cells it infects, and gene therapy takes advantage of this capability. When viruses are used as a way of delivering gene therapy to cells, they are engineered so they do not cause disease. They are stripped of their pathogenic content, and are then altered to carry normal human DNA. These viruses are called “carrier vectors”. The creation of the carrier vectors in the 90’s and the consequent proof of their efficiency and safety, have led to major medical breakthroughs.
Gene therapy can be administered to cells within the body (in-vivo gene therapy), or administered to cells that have been isolated from the body and are reintroduced after the gene therapy occurs (ex-vivo gene therapy).
Researchers are using several different types of viruses as vehicles to deliver gene therapy:
Adeno-Associated Virus: Harmless viruses that do not cause disease. Their DNA does not integrate into the genome of the host cell.
Adenovirus: The virus that causes the common cold is a type of Adenovirus. Their DNA does not integrate into the genome of the host cell.
Retroviruses: Such as Human Immunodeficiency Virus or HIV. This class of viruses can integrate their genome into the chromosomes of host cells. They can only infect dividing cells.
Lentiviruses: A sub-species of Retroviruses. Like all Retroviruses, they can integrate their genome into the chromosomes of host cells, but they also have a unique ability among Retroviruses of being able to infect non-dividing cells. This ability makes them one of the most efficient methods of a gene therapy delivery.
The use of those vectors in gene therapy treatments varies according to their special characteristics. For oncology related diseases Adenoviruses and Retroviruses are used. Adenoviruses are also used for Cardiovascular diseases. Adeno-Associated Viruses are used for the treatment of CNS and Eye and Muscle diseases. Lentiviruses and Retroviruses are used for the treatment of hematological diseases.
Gene therapy in primary immunodeficiency diseases
Primary immunodeficiency diseases are a group of more than 350 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are caused by hereditary or genetic defects. Because the most important function of the immune system is to protect the body against infection, patients afflicted with immunodeficiency diseases have an increased susceptibility to infection and are doomed to endure recurrent health problems, often developing life-threatening illnesses.
Primary immunodeficiency diseases, as a general rule, are better suited for gene therapy than almost any other class of genetic disease. Up until the introduction of gene therapy, several types of immunodeficiency diseases were successfully cured by transplantation of hematopoietic stem cells (bone marrow) taken from a donor with a normal immune system. Therefore, it should be theoretically possible to take the patient’s own hematopoietic stem cells (HSC), correct the genetic defect in them by adding a normal copy of the gene that is causing the disease, and returning them to the patient.
To perform gene therapy, the patient’s HSCs are first isolated from the bone marrow or from peripheral blood, and they are then cultured in the laboratory with the virus containing the gene of interest. After two to four days, the cultured cells are transfused into the patient. The cells that have incorporated the gene of interest into their chromosomes will pass it to all cells that will be generated when these cells divide. Because the gene has been inserted into HSC, the normal copy of the gene will be passed to all blood cell types, but not to other cells of the body. Because primary immunodeficiency diseases are caused by gene defects that affect blood cells, this can be sufficient to cure the disease.
While gene therapy obviously represents a life-saving alternative for patients with severe forms of primary immunodeficiency diseases who do not have a matched donor, it also has indisputable advantages over bone marrow transplant from a donor.
Gene therapy performed ex-vivo (which is the case with immunodeficiency disorders) is considered a safer method, because the manipulation can be monitored in the lab before the cells are returned to the patient, making sure they will not cause harm once returned. Furthermore, a correction the patient’s own HSC does not expose him or her to the risk of developing Graft-versus-host Disease (GvHD), a condition in which the new bone marrow immune cells attack the recipient’s tissues.
The status of gene therapy around the world
Over the last decade, substantial progress has been made in the field of gene therapy, which reflects the growing demand for gene therapy around the world. Several gene therapy treatments have been approved by regulators in the USA and in Europe. These treatments address several terminal conditions that had no cure, and their beneficial effect is considered durable. For example, in 2016 European regulators approved Strimvelis, the first ex-vivo stem cell gene therapy used to treat patients with an immunodeficiency disease called ADA-SCID (Adenosine deaminase deficiency-severe combined immunodeficiency), also known as the “bubble child” disease. Strimvelis has turned a disease with a 0% survival rate into a disease which is 100% curable.
In December 2017, the FDA also approved the first non-CAR T-cell gene therapy for the treatment of a rare inherited form of vision loss. The National Health Service (NHS) in the UK announced in October 2017 a decision to fund gene therapy for the treatment of ADA deficiency in children at a cost of more than £500,000 for the single treatment. In light of the recent developments and the success of clinical trials around the world, it is reasonable to assume that the number of gene therapy treatments which receive regulatory approval will continue to rapidly grow.
The history of gene therapy in immunodeficiency disorders
Until now, gene therapy has been used to treat patients with SCID secondary to Adenosine deaminase (ADA) deficiency, X-linked SCID, CGD and WAS. The first clinical trial of gene therapy took place at the US National Institutes of Health in 1990. It was designed to treat a 4-year-old girl with ADA deficiency. The first trial did not attempt to correct the defective HSC, only the T-cells. More than 20 years after the treatment, the girl is still clinically well and still has about 25% of her circulating T-cells carrying the corrected ADA gene. After this initial clinical trial demonstrated that gene therapy could be carried out safely and that gene-corrected T-cells could survive for years and function normally, follow up trials were initiated attempting to cure children with ADA-SCID by targeting HSC for gene correction. The results have been phenomenal: more than two dozen ADA-SCID patients attained a significant long-lasting increase of the T- and B-lymphocyte count and a remarkable improvement in the functioning of the immune system. Notably, the patients treated did not develop leukemia or any serious adverse reactions.
The next primary immunodeficiency disease to be treated by gene therapy was X-linked SCID. This trial also targeted the HSC using a retrovirus to deliver the gene. Beginning with a groundbreaking study in Paris followed by a similar experience in London, there have been 20 X-SCID babies around the world that have been treated with gene therapy. In these infants, gene therapy was performed without any need for chemotherapy prior to the transfusion of HSC that had been cultured with the virus. Eighteen of these patients are currently alive, and in 17 of these 18 children gene therapy alone was sufficient to restore development of T-lymphocytes and immune function and no other treatment was needed. Unfortunately, while the SCID was cured, five of these patients developed leukemia. Four of the children’s leukemia was cured, but one child died.
In 1999, a 19-year-old boy called Jesse Gelsinger died during a clinical trial for gene therapy. Gelsinger suffered from an X-linked genetic disease of the liver, the symptoms of which include an inability to metabolize ammonia. Gelsinger joined a clinical trial run by the University of Pennsylvania that aimed at developing a treatment for infants born with the severe form of the disease. Gelsinger was injected with an adenoviral vector carrying a corrected gene, and died four days later. This unfortunate event caused public turmoil and was a severe setback for scientists working in the field. All subsequent clinical trials in humans were cancelled. But eventually, the close examination of the faults in that tragic case and others led to the development of safer carrier vectors. One type of such virus which is now commonly in use is the Adeno Associated Virus (AAV). These are harmless viruses that do not cause immune reaction, and do not integrate into the genome of the host cell. Another common alternative is the Lentivirus, which does integrate into the genome of the host cell, but was manipulated to prevent it from integrating into problematic genomic locations. This recent development was a major breakthrough, because it enabled scientists to start using the Lentivirus which has important advantages as a carrier, such as the ability to infect many different types of cells and to carry more DNA than the AAV can.
Hand in hand with scientific developments, regulations for clinical trials in humans were re-written, with higher standards of safety for participants. After a prolonged stalemate, the field of clinical trials was given a second chance. It is now safe to conclude that the new carrier vectors are more effective and safer.
In recent years, a number of centers specializing in gene therapy were founded in the USA and in Europe. These centers are run by leading scientists and doctors and receive significant research funding. Over the last decade, these centers have published the results of several successful clinical trials in a number of genetic diseases. Some of these trials use AAV carriers to cure organs such as the liver and the eye, and some use Lentiviruses to correct hematopoietic cells ex-vivo. Following is a partial list of the results of those trials:
In 2009, Science magazine published a summary of a clinical trial conducted on two children suffering from X-linked adrenoleukodystrophy (ALD), a genetic disease that affects the nervous system and the adrenal glands. People with this disease often have progressive loss of the fatty covering (myelin) that surrounds the nerves in the brain and spinal cord. The standard treatment for this disease is bone marrow transplant, but due to the lack of matched donors for the two children involved, their own bone marrow was corrected ex-vivo using Lentivirus. Fourteen months after the procedure was conducted, a new immune system was created and the loss of myelin in the nervous system was brought to a halt.
In 2013 Science magazine published the results of a clinical trial involving 3 people suffering from Wiskott-Aldrich syndrome (WAS), a rare primary immunodeficiency syndrome. All 3 patients showed dramatic improvement. The trial was a successful demonstration of the feasibility of the use of gene therapy with the new and improved carrier vectors. Another important study published by Science over the same year reported that gene therapy was able to stop children carrying mutations in the gene ARSA from inevitably developing Metachromatic leukodystrophy (MLD), another condition affecting the nervous system.
All the clinical trials mentioned above used Lentiviruses to insert normal copies of genes into hematopoietic stem cells. Numerous studies using this technique were published since 2013, and it receives growing interest of the academic institutes and the pharma industry.
HHS - characteristics and current research
Primary immunodeficiency diseases are rare, chronic disorders in which part of the body’s immune system is missing or functions improperly. These diseases are caused by hereditary or other genetic defects, and most are present at birth or develop in early childhood. The defect in the immune system varies according to the specific genetic mutation that causes the disorder. Those suffering from such disorders have extremely weak immune systems, and are susceptible to all sorts of infections. They often develop serious, life-threatening disease.
Hoyeraal-Hreidarsson syndrome (HHS), the syndrome Noga Baumatz was diagnosed with, is a very rare x-linked recessive disorder considered to be a severe variant of Dyskeratosis congenita (DC). The disorder is characterized by growth retardation, progressive combined immune deficiency, susceptibility to infections, and proneness to cancer. Only about 30 other people worldwide suffering from the same syndrome have been reported up to date, but the disorder may be underdiagnosed due to high mortality rate, and lack of knowledge among medical professionals.
The disorder is caused by a mutation (defect) in the RTEL1 gene, which normally provides the code for making a protein responsible for preserving the length of the telomeres. The telomeres are the caps at the end of each strand of DNA that protect the chromosomes from becoming too damaged and frayed in the process of cell division (much like the plastic tips at the end of shoelaces).
Our cells replenish by dividing themselves, and they do so throughout our lives. Each time the cell divides, the telomeres get shorter, keeping the important DNA intact. Eventually the telomeres get too short to do their job, causing the cell to stop functioning properly. This is a natural process of aging.
Telomeres always shorten with age, but people suffering from HHS are born with extremely short telomeres, making their biological age very different from their chronological age. In such cases, the cells ability to replenish is stunted, and the major effects are felt particularly in systems that are characterized by high frequency of cell division, such as the digestive system and the blood system. This, in turn, compromises the body’s immune system.
The life expectancy of people suffering from the disorder is 3-15 years. During the first years, the causes of death are related to the malfunctioning of the immune system. Respiratory infections can severely deteriorate and become life-threatening. Later in life, death occurs due to cancer, lung fibrosis, liver cirrhosis, and – less frequently – calcification of the nervous system.
Recent developments in the field of gene therapy opened the prospect of finding cure to all kinds of genetic disorders. But the number of genetic disorders is huge, and so far, only a few have had special gene therapies developed for them. This is where we enter the picture: our laboratory and our research team are dedicated to finding the right gene therapy treatment customized to treat and heal HHS.
What we have achieved so far and our future plans
Our research team, working closely with well-known experts, has designed several versions of lentiviruses that contain a normal, functioning copy of the RTEL1 gene. Our next step is to infect stem cells taken from Noga’s blood with these versions of lentiviruses, and examine each versions’ performance. After the infection, the stem cells will be put in an incubator and kept in optimal conditions for several weeks. During those weeks, the researchers will measure the length of the telomeres and the cells ability to divide. The lentivirus version which will outperform the rest in its ability to maintain the telomeres length and restore the ability of the cells to divide will be selected for mass production in a specialized factory. The lentiviruses, will be first tested for safety, by transducing stem cells taken from Noga’s blood, which – in their turn – will be transplanted in mice.
We hypothesize that the stem cells transplanted in the mice will produce enough normal hematopoietic cells within weeks. Such results will be indicative of the success of the clinical trial. If the trial succeeds and satisfies the safety measures previously defined by medical experts, it will be possible to move on to the next step, which is to return the manipulated stem cells into Nog’s blood. The process will qualify for Compassionate Use - the term used to refer to the treatment of a seriously ill patient using a new, unapproved drug when no other treatments are available.