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Inhibitory drugs

Inhibitory drugs

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.

The world's first clinical trial in using tamoxifen to treat DMD- A joint initiative of A.D.I and Hadassah

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.

Further to the call of A.D.I Organization - A research of Dr. Peleg Hasson and Prof. Irit Weizmann in cooperation with the Haifa Israel Institute of Technology (Technion) and the Weizmann Institute of Science

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.

Further to the call we published in 2017 - An establishment of a system of Cardiomyocytes from patients with Duchenne to scan drugs for the heart and muscles

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.

Scientific and Financial support in Dr. Peleg Hasson's study aiming at the reduction of fibrosis by controlling the dose of the Lysil enzyme.

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.

Testing the effectiveness of new anti-inflammatory substances is being conducted with the initiative and scientific support of A.D.I.

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.

A.D.I Organization in collaboration with researchers from Tel Aviv University - activation of existing genes to prevent collapse of the muscle cell.

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.

In full cooperation with A.D.I. and with its support - Dr. Amir Dori's research on a peptide (small protein) to neutralize the thrombin protein.

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.

At the initiative of A.D.I – treatment with mesenchymal stem cell therapy.

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.

Treatment by exosomes being discharged from mesenchymal cells.

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.

Stem Cell Therapy – Pluristem Therapeutics.

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.