It is known that maintaining a high standard of treatment, tailored to each patient according to his condition, can delay the development of the disease. From the stage of diagnosis, regardless of the patient’s age, it is crucial to begin conservative treatments such as physiotherapy, hydrotherapy, as well as prescribe preservative drugs such as steroids, vitamins or other medications, to ensure proper nutrition and a longer life span. In later stages of the disease, it is very important to have a comprehensive periodical treatment in combination with treatments for maintaining swallowing, breathing and even preserving simple motor abilities such as moving a finger that maintains the patient’s independence. For this purpose, it is very important to keep multi-system clinics specializing in providing a comprehensive response to the various and complex aspects of the Duchenne disease, and in depending on the condition of each patient.
In view of the great importance of receiving individual treatment, rendering to the highest accepted global standard, A.D.I Association currently supports 2 multi- disciplinary local clinics that provide consultation for all DMD patients, at all stages of the disease.
The clinic provides a comprehensive response to young patients from diagnosis stage to the age of 16. The clinic includes a team of physicians and therapists in various disciplinary fields; neurology, lung, cardiology, orthopedics and hysiotherapy. The sharing of information between the various specialists enables the receipt of a comprehensive representation while reflecting the patient’s condition in the early stages of the disease, and enables the specialists provide individually tailored and accurate treatment to each patient amid his condition. It is known that high-standard maintenance treatments can delay the development of the disease and allow young boys more years to walk without needing a wheelchair. In addition, when all the specialists are gathered at the same location, it eases the life of DMD families who can be seen by all physicians without having to be dragged from one clinic to another. We collaborate closely with the clinic and support the completion of vital functions that are not funded by the hospital. This kind of cooperation improves the existing medical treatment and provides an additional and vital way to expand the clinic’s activity and to offering new treatments in the context of compassionate or clinical trials. To contact the clinic at Hadassah and to coordinate a visit kindly call :+ 972 (0)2- 5844751.
In cooperation with Dr. Amir Dori, a neurologist specializing in the treatment of peripheral nervous diseases with an emphasis on the Duchenne disease, we successfully managed to establish in 2016, a multidisciplinary clinic for patients older than 16 years. This clinic is the only one in Israel, today, that provides a comprehensive care. It operates with the cooperation of the neurological clinic as well as other clinics in the hospital, such as the heart failure, pulmonary disease, gastroenterology, orthopedics, rehabilitation, and additional clinics, all allowing the patients to optimally cope with the their highly complex adult patient conditions.
As the disease progresses, the muscle mass decreases and the inflammation of the fibrosis becomes more apparent, other complications arise, usually caused by inflammation. There are also severe side effects caused by the steroids: scoliosis, osteoporosis or other symptoms can occur. The clinic delivers an individualized response to the disease, by providing appropriate cardiologic drugs, osteoporosis treatments, and as much respiratory support as possible, non-invasive, direct feeding to the stomach, and more. All with the aim of preserving vital functions, improving the patient’s quality of life ,reducing pain and prolonging life. In addition to the clinic, an advanced research laboratory was established as well, enabling an advanced and relevant research in cooperation with the patients and under their consent. Since 2016, A.D.I. association , has provided significant support for the establishment of the clinic and its laboratory, the purchase of permanent and expendable equipment, and funding essential positions not financed by the hospital. The tied and effective cooperation with Dr. Dori, enables both the improvement of patients’ medical care and the advancement of research. To contact the Sheba Clinic and set up an appointment, please contact: neurology.mirp@sheba.health.gov.il
A genetic defect creates a deficiency in the production of the dystrophin protein. In the absence of protein, the muscles in the kids’ body are exposed, and they are rotting every day and with every simple motor action. With muscle erosion, a space is created where fat tissue grows. (Fibrosis). Fat tissue is very inflammatory and with the spread of inflammation – severe side effects occur, and concurrent with the progression of the disease is accelerated. There are several different technologies that can inhibit the development of the disease. From technologies that know how to treat the cause of the disease itself, and even to produce some of the missing protein, to technologies that are designed to treat the consequences of the disease.
Tamoxifen is a 30-year generic drug. The drug is given to breast cancer patients. Previous studies have shown that tamoxifen can help patients with Duchenne by reducing fibrosis, boosting cell membranes and slowing disease progression. In 2016, A.D.I submitted the Helsinki applications and after the approval was given, it began in December 2016, the first clinical trial in the world, under the direction of Dr. Talia Waldman Dor, in boys with Duchenne who are over 5 years of age. Following Israel, in 2018, large-scale clinical trials were initiated in Europe and the U.S.
Laboratory results show that preventing the activity of LOX inhibits the development of fibrosis, increases muscle regeneration and improves activity. These results suggest that inhibiting the enzyme can be used as a new treatment to delay the fibrotic process in the disease. In addition, we found that apart from its pro-fibrotic activity (outside the cell), the enzyme also works within the cell and this activity is essential for muscle building. We understand that if we inhibit extracellular activity without disrupting intracellular movement, the muscle regeneration process will take place and in fact the fibrotic process will be delayed. Together with the researchers, we created antibodies to LOX inhibitors that could work only outside the cell. The first results suggest that fibrosis was reduced in model animals and that muscle activity has improved. It is important to note that the delay or deceleration of the fibrosis process is an essential stage in the treatment, because it allows better access to drugs or cells that contribute to optimal muscle regeneration. At this stage we are preparing for a larger trial to guarantee efficacy.
Prof. Ofer Binah of the Technion, in cooperation and with the support of A.D.I. organization, established a system of beating heart cells from patients. The purpose of the system is to scan drugs and treatments that should help the heart and muscles. The system simulates the heart muscles of patients with all types of mutations (Deletion, multiplication, and point mutations). At this stage the system is undergoing characterization and we will soon be able to test the effects of experimental compounds or existing drugs.
Fibrosis are inflammatory scars that are created as a result of the muscle’s demise. Due to the tendency of scars to become inflammatory, an accelerated process of muscle destruction is created. The study examines whether cystic fibrosis can be reduced by controlling the appropriate dose of a protein called lysil oxidase. A first trial under the direction of Peleg Hasson of the Technion, has already been performed in animals and has been proven positive. We are preparing for another trial. Our organization performs all diagnoses and histologists for this trial.
The research was conducted in cooperation with researchers from the Hebrew University. The progression of Duchenne is accelerated by inflammation of the fat tissue (fibrosis). Hence the trial’s objective is to test new anti-inflammatory agents that can significantly slow progression of the disease. The first animal trial was carried out using 2 different materials that yielded promising results. Fibrosis in the diaphragm appears to have decreased significantly (40%) as well as the CPK. Another longer trial is expected soon.
The Organization, in cooperation with Prof. Eda Raphaeli of Tel Aviv University, is examining the HDACI deactivation of histones. We hope that we can activate existing genes that can prevent the collapse of the muscle cell. We expect fibrosis reduction and elevation of the hypotension to a significant improvement in the muscle tissue. The first trial is expected to be completed. After the results are decoded, the next step will be decided upon.
Thrombin is an existing protein in the human body. When muscle damage is caused by the absence of dystrophin protein, thrombin increases damage and accelerates muscle destruction. The purpose of the trial is to neutralize the thrombin protein, and thereby slow the progression of the disease. The first protein-lowering trial was performed, and good results were obtained. We are preparing for another trial.
Mesenchymal stem cells are present in many tissues in the body. These cells were found to be effective in treating various degenerative diseases. It is important to note that the safety of these cells has been demonstrated in many models – preclinical and clinical. The mesenchymal cells secrete many compounds that can improve the condition of damaged tissue by reducing levels of fibrosis and inflammation and increasing the muscle’s ability to regenerate and rehabilitate. When the right conditions occur, those cells can differentiate into normal muscle cells, integrate into the damaged tissue and create healthy muscle tissue. Prof. Haya Brody of Bar-Ilan University is testing mesenchymal cells from different tissues to identify the most suitable cell type for the treatment of Duchenne, and to study the mechanisms by which these cells work. In addition, we are developing new methods for creating appropriate mesenchymal muscle cells to achieve the best therapeutic effect. The tests are done on human muscle cultures of healthy and sick patients, on the Duchenne model in mice. We plan to move to clinical trials as soon as possible.
Exosomes are very small cellular secretions that are secreted by the cell and contain different proteins and nucleic acids. Exosomes are one of the ways in which cells communicate with adjacent ones and affect the environment in which they are located. Duchenne affects many muscles in different parts of the body, so one of the major challenges in developing a drug for Duchenne, is the ability to spread the drug to a enough mass of muscle in the patient’s body. Prof. Brody of Bar-Ilan University uses exosomes secreted from mesenchymal cells, to transfer various compounds to damaged skeletal muscle and heart. Among others we focus on compounds that cause the formation of dystrophin and heterotrophic proteins in the injured muscles, in order to encourage a process in which the muscles can restore the damage caused by the lack of dystrophin.
The tied cooperation of the organization with Pluristem company in order to examine the efficiency of the placenta’s cells on MDX mice. The study aims to prove that it is possible to renew damaged muscle tissue and lower the level of CPK. The first trial showed an impressive drop in the CPK level, and the intention is to begin a longer animal trial based on information from other studies carried out by A.D.I. We hope the trials will be successful, so that clinical trials for kids will be advanced. At current this study does not progress.
The origin of Duchenne is known to researchers. A minor defect in the gene prevents the production of an essential protein – dystrophin. There are various mutations linked to the disease, i.e. two different persons differ in their mutations at the same gene. For instance, Some patients have multiple mutations (there is one or more multiple exon in the DMD gene), others have missing/deleted mutation (one or more exons are absent in the DMD gene) furthermore, there are patients with point mutation.
In all types of mutations the result is the same – the production of the protein is stopped, and the muscles of the patients are exposed and vulnerable. The hope of all Duchenne patients is developing a technology that will know how to repair the defective gene by transplanting or repairing the gene. There are already developments in various stages all over the world and in Israel, which are based on the technology of inserting a normal gene for the implantation of the genetic code that will lead to renewal of the production of the protein.
Some gene therapy technologies are already in a very advanced stage of clinical trials.
In the United States, three companies (Sarepta, Solid and Pfizer) have already begun clinical trials in 2018 to demonstrate the effectiveness of an identical technology that attempts to introduce a micro dystrophin antibody gene to the microorganism gene (AAV). The complex challenges in proving the effectiveness of the technology are adapting the genetic code, which is very large in relation to the virus that should contain it, dealing with the immune system of the body that does not always recognize the virus and can attack it, as well as the ability to cause the virus to spread and reach all muscle cells in the body.
Our leading projects in this field focus on initiating research, providing resources and supporting ongoing research in Israel – in order to get as soon as possible treatment for our boys. At the same time, we are promoting cooperation with international companies in order to bring existing trials to Israel.
This Israeli company is working on developing a revolutionary technology for gene therapy without intervention in the gene itself. Under normal circumstances the protein is produced by the mRNA which is produced from the DNA. In Duchenne patients, since the DNA is damaged, the MRNA is also damaged and the protein is not produced. The company is working on technology to create proper MRNA in the laboratory.
A technology based on insertion shortened micro-dystrophin gene by the AAV virus. It’s highly advanced technology and there are already three companies that have started clinical trials, currently underway in the U.S only. Our goal is to supply the trials to children in Israel as soon as possible. Technology used by the companies mentioned above, has already begun clinical trials and the results are expected to be published during 2020.
In order to promote cooperation and bring this clinical trial to Israel, we are examining the results of clinical trials in France, with emphasis on examining the safety of treatment. At the same time, the procedures for obtaining permits for a clinical trial by the Israeli authorities have already begun. We are working to ensure that our boys in Israel will be among the first children in the world to receive this experimental and revolutionary treatment.
In 2018, the pharmaceutical giant Pfizer began trial treatment as part of a clinical trial in genetic therapy. The technology is based on insertion functional mini-dystrophin gene in cells by AAV virus Insertion functional gene, partial production of the dystrophin protein is expected, hoping that the disease progression will slow significantly. Pfizer expressed their willingness to cooperate with A.D.I and to include Israel in a clinical trial – phase III. The negotiations between Pfizer and us are currently ongoing in order to bring the trial to Israel as soon as possible.
The research group headed by Prof. Karni is working on the development of new molecules that will be able to change the base sequence in RNA molecules in patients with DNA deletions or duplications. The logic, which is very similar to the developments already in clinical trials, translating shorter dystrophin protein but still functional. The study is still at the examining cells stage; However, there are new discoveries and impressive progress that has been made. Nevertheless, the road is still long…
Duchenne patients have a mutation in the gene encoding the dystrophin protein. The DNA, which is the hereditary material, is transcribed into RNA and from the reading sequence, it is translated into the dystrophin protein. Due to the defect in the gene, RNA is improperly reproduced and therefore decomposed, and protein is not produced. The study is working on new molecules that can delay the dissolution of existing RNA molecules for patients with point mutations.
We interpret the experimental results for the research group. The first trial ended successfully. An additional one, which will include a combination of approved drugs, is expected to begin. Our goal is to proceed as quickly as possible to pediatric clinical trials.
The study aims to identify several chemical molecules that represent active substances taken from the patients themselves, in order to quantify the protein level, to characterize the pharmacological effect of the molecule, and to locate biologically active substances that are specifically directed to the patients’ cells. We hope that positive outcomes will guide us toward an era of effective treatment for every single patient.
