Gene therapy against diabetic foot
Konstantin Filatov, AMI-TASS
The incidence of diabetes mellitus is growing both in Russia and around the world. the pace is impressive – according to forecasts, by 2030 about half a billion people will be ill with diabetes in the world. This disease is dangerous both by itself and by its complications, one of which is diabetic foot syndrome (DFS), which leads to a high percentage of disability and mortality. In this regard, it is necessary to introduce new methods of treatment of diabetes mellitus and its complications. One of the latest developments is gene therapy using a drug that stimulates the growth of new collateral vessels in the affected limb. The Ministry of Health of the Russian Federation has issued a permit to conduct clinical trials of the drug Neovasculgen for the treatment of SDS.
"The plague of the XXI century" and its complications
According to the Ministry of Health of Russia, in 2015, the number of diabetic patients in Russia amounted to about 4.5 million people. Even according to official data, Russia is among the countries where the incidence of diabetes is close to the epidemiological threshold, while experts believe that the real number of cases in Russia is significantly more than official statistics show and reaches 9 million people.
Doctors call diabetes mellitus the "plague of the XXI century." According to WHO, the incidence rate in the world has increased 4 times over the past 30 years, and an increasing number of young people are becoming ill with diabetes. The main increase in cases occurs due to type 2 diabetes, which is often characterized as a lifestyle disease. 80-90% of diabetic patients suffer from this form of the disease. And if earlier type 2 diabetes was diagnosed mainly in people over 45 years old, now it affects more and more young people.
3.8 million people die every year from complications of diabetes mellitus on the planet. The disease destroys blood vessels, so the main complications are SDS, vascular pathology of the heart, diabetic retinopathy (blindness associated with impaired blood supply to the retina). Moreover, in terms of the prevalence and number of undesirable outcomes, the diabetic foot is the leader in this list. According to statistics, the prevalence of this pathology among patients with diabetes mellitus is 5-10%. Moreover, patients with SDS account for 60% of all lower limb amputations of a non-traumatic nature.
The appearance of SDS and ulcerative defects is caused by a number of destructive processes in the patient's limb, among which pathomorphological changes in the walls of the vessels of the microcirculatory bed play an important role. Sometimes endothelial hyperplasia reaches a complete blockage of the lumen, after which the capillary ceases to function, which leads to necrosis of the tissues of the patient's extremities. In Russia, according to official statistics, about 30 thousand high amputations of the lower extremities associated with VDS are performed per year.
How to treat
The most common method of treating SDS is surgical revascularization, that is, an operation to restore the lumen of the arteries of the lower extremities using balloon catheters and stents, the purpose of which is to create direct blood flow through the arteries to the affected area on the foot for the period of healing of an ulcer or wound. In fact, surgical methods of treatment are similar to those used for chronic and critical ischemia of the lower extremities.
The dependence of the disease on the state of the circulatory system suggested that the induction of angiogenesis (the growth of new vessels) and the restoration of blood microcirculation in tissues will improve the regeneration process. The instrument of such treatment can be gene therapy, carried out with the help of innovative drugs, one of which is Neovasculgen, a drug created by the Human Stem Cell Institute (HSCI) and registered in Russia five years ago. It is successfully used to treat lower limb ischemia. Its active component is a plasmid, a double–stranded DNA molecule containing the VEGF 165 gene encoding the synthesis of vascular endothelial growth factor protein.
The mechanism of action of Neovasculogen is as follows: after the introduction of the drug into the muscle tissue, it penetrates into the cell, functions for 10-12 days, while not embedded in the genome and then removed from the body naturally.. In muscle cells, the DNA molecule begins to express the vascular endothelial growth factor gene, which, in turn, increases the concentration of the main growth factor. The development of collateral vessels begins, and, as a result, the improvement of blood microcirculation.
What was done
Before proceeding to evaluate the effectiveness of gene therapy for diabetic foot syndrome, the HSC conducted preclinical trials, during which it was proved that the introduction of Neovasculgen into the affected tissues of an animal with diabetes stimulates the growth of microcirculatory vessels, which reduces the time for wound closure.
After preclinical trials, pilot clinical trials were organized to evaluate the efficacy and safety of the drug. It was attended by patients with neuroischemic form of SDS, who could not perform revascularization surgery (and half of the patients still used surgical interventions), and standard therapy did not give results. The average age of patients was 62 years, the duration of diabetes was 12 years. An important factor was the lack of positive dynamics in the picture of the disease over the past 4.5 months.
According to Igor Plaksa, a researcher at the ISKCH, pilot studies of the drug's effect on the diabetic foot were conducted on the basis of the Ryazan State Medical University and at the regional clinical hospital of the city of Vidnoye. 35 patients participated in the trials, and the follow-up period was 6 months with control periods 30, 90, and 180 days after administration of the drug. The drug itself was injected into the muscles of the lower leg on the first and 14th days after the start of the experiment.
According to the test results, the healing of ulcerative defects caused by SDS occurred in 65% of patients. Three patients had to perform a large amputation of the lower extremities due to complications, however, the results of the experiment suggest that the gene induction of angiogenesis in SDS reduces the healing time of the ulcerative defect and is able to improve the quality of tissue regeneration if surgical intervention is impossible.
Similar studies were conducted in 2013-2014 in the Department of Vascular Surgery of the I.I.Janelidze Research Institute of Emergency Medicine (St. Petersburg). There were 12 patients with chronic arterial insufficiency of the lower extremities under observation, who were injected with Neovasculgen. The age of the patients ranged from 55 to 76 years (the average age was 66 years), among whom there were 8 men (66%) and 4 women (33%). The condition for performing injections was the presence of chronic obliterating diseases of the lower arteries with a multi-storey lesion of the vascular bed, or the absence of a distal vascular bed or severe concomitant pathology, and as a result, performing reconstructive interventions on the arteries was impossible. In all cases, the etiology of the disease was atherosclerosis, of which 5 (42%) patients had diabetes mellitus.
During examination at control visits 3 and 6 months after administration of the drug, an improvement in the microcirculation of blood flow in the lower extremities was found in 90% of patients. According to a team of authors from the I.I. Janelidze Research Institute of Emergency Medicine, "no adverse events, adverse reactions, complications were noted when performing injections of the Neovasculgen drug. The administration of the drug was painless, no local reactions were noted."
Igor Plaksa explains this as follows: "The plasmid is rapidly destroyed in the bloodstream, its component is not identified by the end of the first day, which means that this drug can be characterized as a local inducer of angiogenesis that does not have a systemic effect. In addition, Neovasculgen does not affect the progression of diabetic retinopathy, therefore it is safe for this category of patients, and can be used in the treatment of SDS as one of the effective methods of therapy for this disease."
Alexey Fokin, president of the Euro-Asian Association of Angiologists and Vascular Surgeons, also confirmed to RIA AMI the prospects of treating SDS with Neovasculgen, noting that such therapy is already underway and fully justifies itself.
What is to come
Successes in the treatment of VDS led to the fact that in November 2016, the Ministry of Health of the Russian Federation issued the HSC permit No. 737 to conduct clinical trials of Neovasculgen in order to assess the effectiveness and safety of its use in patients with VDS. 99 patients will participate in the study until March 1, 2018.
Clinical trials are expected to be conducted on the basis of the following organizations: FSBI "Endocrinological Research Center" of the Ministry of Health of the Russian Federation, GCB 15 named after Filatova, Northwestern Federal Medical Research Center named after V.A. Almazov, Ryazan Regional Clinical Cardiology Dispensary.
Artur Isaev, Director of the ISHR, commented on the actions of the Ministry of Health: "The drug has shown good results in the treatment of lower limb ischemia. The obtained permission gives us the opportunity to expand the indications of its use. In case of successful clinical trials, Neovasculgen will become available for patients with diabetic foot syndrome."
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09.12.2016