JP2001327598A - Genetic therapeutic agent injection device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a gene therapeutic agent injection device which is capable of controlling the cooling temperature, injection rate and injection speed of a gene therapeutic agent, stabilizes the activity and injection conditions of the gene therapeutic agent, relieves an operator from the restriction on time and allows the safe and efficient injection of the gene therapeutic agent and to provide the gene therapeutic agent injection device which three-dimensionally and effectively diffusing the injection of the gene therapeutic agent when introducing the genes into the lesion tissue varying with each of cases and is capable of reducing the use of the precious and costly gene therapeutic agent to the least necessary extent. SOLUTION: The gene therapeutic agent injection device is provided with an injection means for the gene therapeutic agent having a cooling means and a pump controller connecting this injection means. The control of the cooling temperature, injection rate and injection speed of the gene therapeutic agent is made possible by the pump controller.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an apparatus for injecting a gene therapy agent locally into an affected tissue, which is used in gene therapy for cancer or the like.

[0002]

2. Description of the Related Art Cells constituting the human body repeatedly undergo proliferation and death under a certain control to maintain the function of each organ. However, if these cells acquire disordered autonomous proliferation ability for some reason, they become malignant. Collectively referred to as neoplasms (cancer or sarcoma). The cause of carcinogenesis is gradually elucidated by recent advances in molecular biology to be caused by some genetic abnormality. In particular, it has been revealed in various cancers that normal cells become cancerous due to activation of oncogenes and abnormal functions of tumor suppressor genes, and cancers are being regarded as genetic diseases.

[0003] Cancer occurs in most organs constituting the human body. Thus, the disordered autonomous growth of cancer cells
Causes impairment of normal organ function. Further, as the cancer cells proliferate, the cancer cells spread invasively from the site of origin (primary lesion) to surrounding tissues, move on to the bloodstream or lymph stream, move to another site, and proliferate there. That is, invasion and distant metastasis are biological characteristics of cancer. Invasive and metastatic growth causes pain that is difficult to control (cancer pain), causes deterioration of nutritional status (cancer cachexia), and ultimately leads to death of the individual. Cancer (malignant neoplasm) is the leading cause of death in Japanese, accounting for 30% of the total deaths, followed by 15% of heart disease and 14% of cerebrovascular disease
It is. It is needless to say that the control of cancer as an important issue in public health is a major issue imposed not only on Japan but also on the human race in the 21st century.

In recent years, the mortality rate due to gastric cancer has decreased, and the mortality rate due to lung cancer, colon cancer, and prostate cancer has increased. About 300,000 men are diagnosed with prostate cancer each year in the United States and about 40,000 people die, suggesting a link between fat intake and carcinogenesis. In fact, with the westernization of dietary habits, deaths are increasing faster than expected in Japan.
Treatment methods for cancer are basically classified into a) surgical treatment, b) radiation therapy, and c) anticancer chemotherapy. Each treatment method is selected according to the type of cancer and the progress state (stage) of the cancer.

[0005] a) Surgical treatment is classified into radical surgery and non-radical surgery. Curative surgery is indicated for early stage cancer in principle. Non-radical surgery is considered a volume reduction of cancer lesions for the purpose of improving impaired organ function or subsequent additional treatment. Surgical cure is the surest measure,
The indication is limited, and early detection is a key point. Even if considered a radical operation, postoperative recurrence most determines the prognosis of the patient. Enlarged surgery, which seeks further curative treatment, is associated with a post-operative quality of life (Q)
The challenge is to tackle the conflicting event of developing techniques to maintain quality of life without compromising curability to compromise OL).

B) Radiation therapy is selected based on the sensitivity of the cancer cells to radiation. Uterine cancer, testicular cancer, pharyngeal cancer, breast cancer, etc. are the main targets as highly sensitive cancers. However, there are few cases that can be cured alone, and it is frequently used as a combination therapy. Despite improved methods of irradiation, early or late damage due to irradiation is often severe and is a major limitation of this treatment.

[0007] c) With respect to anticancer chemotherapy, susceptible drugs are administered alone or in combination. Even for advanced cancers, highly sensitive cancers that may lead to cure are limited to leukemias, malignant lymphomas, testicular cancers and the like.
For anticancer chemotherapy for many other cancers, although a temporary tumor suppressive effect has been confirmed, few treatments have been confirmed to significantly improve prognosis. In addition, side effects due to treatment are also a major problem.

[0008] At present, early detection and early treatment are the most reliable methods to cure the disease, and it is a reality that a cure that can cure radically advanced cancer in only limited carcinomas is being developed. To break through this situation,
The development of an effective and safe treatment alternative to the above-mentioned treatment has been expected. The causes and pathological conditions of cancer have been elucidated at the genetic level, and with the advancement of technology related to genetic manipulation, the possibility of treating cancer at the genetic level has become a reality.

[0009] Against this background, gene therapy, which is a state-of-the-art medical treatment for treating diseases such as cancer by introducing a gene into cells in the body, has been proposed in the United States since around 1990, and in recent years, it has been attempted in Japan. It is becoming.
For example, gene therapy based on the molecular pathology of cancer is being applied to cases in which anticancer drugs do not work and many of them recur in other therapies. At the present time, although safety is mainly confirmed, there are reports of clinical trials that have been confirmed to be effective, and it is expected that more effective gene therapy methods will be established in the future.

[0010] The principle of gene therapy is to efficiently introduce a gene intended to be introduced into target cells. As the gene therapy agent, a liposome containing a gene, a cell into which the gene has been introduced, and the like can be used.The gene is usually incorporated into a “carrier” called a vector, and the vector is inserted into the target cell or tissue. Make contact. Various vectors have been developed,
Viruses are often used as vectors. Adenovirus is mainly used as a vector in terms of simplicity of adjustment, safety, and introduction efficiency. Adenovirus is known as a virus that causes colds in infants.
For more than 0 years, approximately 1 million soldiers have been administered adenovirus as a vaccine and their safety has been confirmed. In addition, safety when used in gene therapy has been generally confirmed.

[0011]

As described above, gene therapy for cancer and the like has attracted attention as an innovative therapy, but several problems have been pointed out in this gene therapy. That is, in the conventional technique, since the gene is introduced by manual pressure injection, the required pressure and required time for the injection are not reproducible, and the injection is different every time the injection is performed. In addition, since a gene therapy agent such as a viral vector incorporating a gene may be deactivated in about 30 minutes by being taken out of a cooled state to room temperature when the gene is introduced, the gene therapy agent may be charged into a syringe and an injection needle. There is a significant time limitation in the operation, as well as the subsequent puncture of the cancer by ultrasound guidance. Furthermore, since the condition of the affected part is different for each case, there is a difference in puncture time, etc.
The stability of the gene therapy agent must be injected under different conditions.

Therefore, the present invention makes it possible to control the cooling temperature, the injection amount and the injection rate of the gene therapy agent, stabilize the activity and the injection conditions of the gene therapy agent, and relieve the operator from time constraints. An object of the present invention is to provide a gene therapy drug injection device that enables safe and effective injection of a gene therapy drug. In addition, the present invention provides a three-dimensional and effective diffusion of the gene therapy agent when introducing a gene into an affected tissue that differs from case to case, and minimizes the amount of valuable and expensive gene therapy agents used. It is an object of the present invention to provide a gene therapy agent injection device that can perform the treatment.

[0013]

The apparatus for injecting a gene therapy agent of the present invention has the following structure to achieve the above object. (1) An apparatus for injecting a gene therapy agent, comprising: means for injecting a gene therapy agent having a cooling means; 2. The gene therapy injection device according to 1, wherein the pump control device is capable of controlling a cooling temperature, an injection amount, and an injection speed of the gene therapy agent. (3) The gene therapy drug injection device according to (1) or (2), wherein the gene therapy drug injection means includes a metal injection needle having a closed sharp tip and a side hole at the tip. (4) The means for injecting the gene therapy agent has a flexible injection tube connected to the injection needle, and the injection tube is separated into a front injection tube and a rear injection tube by a three-way switching valve, 4. The gene therapy agent injection device according to 3, wherein a cooling tube is provided on an outer peripheral portion of the front injection tube. 5. The gene therapy agent injection device according to 4, wherein the cooling temperature of the gene therapy agent is monitored and controlled by a temperature sensor provided in the front injection tube. (6) The gene therapy agent injection device according to (4) or (5), wherein a check valve is provided at a connection between the front injection tube and the three-way switching valve.

[0014]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS An embodiment of the present invention will be described below with reference to the drawings, taking a micro-quantitative gene injection apparatus for injecting an aqueous vector solution as a gene therapy agent into prostate cancer as an example. 1 to 8 show one example of the gene injection device of the present invention.
FIG. 1 is a schematic view showing the configuration of the entire apparatus, and FIGS. 2 to 8 are partially enlarged views showing members constituting the apparatus of FIG.

This micro high-quantity type gene injection device is connected to the syringe pump control device 1 via a syringe pump control device 1 and a syringe 4 (A in FIG. 1; an enlarged view is shown in FIG. 6). It comprises a tube 3, a three-way cock 2, a tube 5 for injection on the front side, and an injection needle 6. Also,
The front side injection tube 5 is formed of a double-structured tube for circulating the cooling water to the outer peripheral portion, and the outer peripheral portion is connected to the cooling device 11 by the cooling water circulating tubes 8a and 8b.

FIG. 2 is an enlarged view of an injection tube (portion B in FIG. 1). The three-way stopcock 2 provided at the center of the tube for injection has three ports.
Is connected to the rear injection tube 3 by the connection lock connector 2a. Also, the second port is
Although connected to the front injection tube 5 by the connection lock connector 2b, a one-way valve 2c for passing only the flow toward the front injection tube 5 is incorporated in the second port for the purpose of preventing infection. Have been. The third port is used for filling a physiological saline solution or a vector aqueous solution into which a gene is incorporated. The third port is filled with a vector aqueous solution or the like from a filling port 2d by a micro syringe or the like (not shown).

The front injection tube 5 is constituted by a double-structured tube for circulating the cooling water to the outer peripheral portion, and connected to the cooling water circulating tubes 8a, 8b by connection ports 5a, 5b provided at both ends. Connected. A temperature sensor 9 is provided in front of the connection port 5c to the injection needle 6, and measures the temperature of the aqueous vector solution injected into the diseased tissue 7. Further, the front side injection tube 5 can exchange expensive and valuable vector aqueous solution by exchanging tubes having different inner diameters and total lengths according to the standard of the injection needle 6 to be connected and the target injection amount of the vector aqueous solution. Usage can be minimized.

To fill the injection tube with the vector aqueous solution, first, the connection between the front injection tube 5 and the rear injection tube 3 is cut off by the three-way cock 2, and the filling port 2d and the rear injection tube 3 are connected. After the connection, the syringe 4 is pushed out from the filling port 2d through the rear injection tube 3 and filled with physiological saline used for injection. Next, the three-way cock 2 is switched to connect the filling port 2d to the front injection tube 5, and the vector needle solution is filled into the injection needle 6 from the filling port 2d via the front injection tube 5.

The filled aqueous vector solution is cooled by cooling water circulated through cooling water circulating tubes 8a and 8b connected to the outer periphery of the front injection tube 5. The temperature of the vector aqueous solution is monitored by the temperature sensor 9 and controlled within a predetermined temperature range. To inject the vector aqueous solution into the diseased tissue 7, the three-way cock 2 is switched so that the rear injection tube 3 is replaced with the front injection tube 5 and the injection needle 6.
Communicate with Next, the affected tissue 7 is filled with a predetermined amount of the vector aqueous solution by pushing out the physiological saline in the syringe 4 by operating the syringe pump control device 1.

The syringe pump control device 1 of the present invention injects a small aqueous vector solution to be injected while cooling it to an arbitrary temperature in an injection tube.
Therefore, there is provided a means capable of injecting a predetermined amount at a predetermined rate while maintaining the activity of the viral vector until the injection, based on temperature information sent by, for example, a temperature sensor. Therefore, as long as such an object can be achieved, various injection pumps and a cooling device controlled by a compressor using Freon gas as a cooling medium can be used. According to the study of the present inventor, a device equipped with a small syringe and a cooling device that does not require a compressor using a Peltier element as a cooling medium is preferable because it can easily cope with injection and cooling of a small vector aqueous solution. Also, since the system can be easily miniaturized and simplified, it is extremely preferable in this respect as well.

FIG. 3 is an enlarged view showing an example of a syringe pump control device 1 of a minute high-quantity type used in the device of FIG. In this device, the temperature information of the vector aqueous solution in the injection tube taken in by the temperature sensor 9 is continuously displayed by the injection control unit 10, and the cooling device 11 is controlled based on the information. It is preferable to have the function of displaying the temperature information as described above, since the state of the activity of the vector aqueous solution can be visually confirmed. However, such a display unit may not be provided. In addition, the injection control unit 10 can arbitrarily set an injection amount and an injection speed that may be different for each case, and the movement amount and the movement speed of the piston incorporated in the injection unit 12 are determined by setting the injection amount. . Then, the injection of the aqueous vector solution is set so that the injection can be performed only within an arbitrarily set temperature.

FIG. 4 shows details of the injection control section 10 shown in FIG. The setting of the injection amount and the injection speed is performed by a single injection amount setting button 10a and an injection time setting button 10b, and the required pressure in the injection is indicated by an injection pressure display section 10c.
You can check at. In addition, the temperature of the cooling aqueous solution in the front injection tube 5 measured via the temperature sensor 9 is monitored by the injection temperature display unit 10d.

Next, FIG. 5 shows details of the cooling recirculation device 11 of FIG. The cold water in the chamber 11b cooled to the target temperature by the setting of the temperature setting unit 11a
1c, which is guided by a reflux pump 11d which is movable, flows through the outer peripheral portion of the front injection tube 5 by the cooling water reflux tubes 8a and 8b, and returns to the chamber 11b again.
Reflux to be sent back into.

Further, details of the injection section 12 shown in FIG. 3 are shown in FIG.
Shown in The injection unit 12 has a syringe holder 7a for mounting the syringe 4 and a piston holder 7c for holding the piston 7b, and the piston inside the piston holder can be moved back and forth by an internal motor. When the piston is retracted, the physiological saline is sucked into the syringe, and when the piston is advanced, the physiological saline is sent out.
At this time, the vector aqueous solution filled in the front injection tube 5 and the injection needle 6 is pushed out. The amount of liquid sent out from the syringe by the movement of the piston is 0.1 to 3.0.
Set to about ml / 1 time.

FIG. 7 is an enlarged view of the syringe 4 used in the injection device of the present invention. The syringe 4 is provided with a hard piston head 4a with little damping in order to perform minute high-quantity injection. It is preferable to provide a lock connector 4b at the rear end of the syringe 4 for connecting to the piston holder. Further, it is preferable to provide a lock connector 4c at the distal end of the syringe 4 in order to connect to the rear injection tube 3. The dimensions of the syringe 4 can be set arbitrarily, but usually a small one with an inner diameter of 16 mm, a cross-sectional area of 2 cm ² and a capacity of about 5 ml or less is suitably used.

FIG. 8 is an enlarged view of the injection needle 6 suitably used as the injection means in the present invention. This injection needle 6
Is made of metal and processed so as to respond to use under an ultrasonic echo. The tip is sharply closed and a side hole 6a is provided at the tip. This side hole 6
It is preferable to provide a plurality of “a” in order to three-dimensionally and effectively diffuse the aqueous vector solution to be injected into the affected tissue 7. Further, it is preferable to provide a lock connector 6b connected to the front injection tube 5 at the rear end of the injection needle 6. The dimensions of the injection needle 6 can be arbitrarily selected. In this example, the diameter is 22 Gφ and the total length is 20 cm.

In the above specific example, a micro high-quantitative gene injection apparatus for injecting a vector aqueous solution as a gene therapy agent into prostate cancer has been described. However, the present invention is not limited to the above specific example, and the present invention is not limited thereto. For example, it can be applied to hepatitis, emphysema, arteriosclerosis, hemophilia, diabetes, Alzheimer's disease and the like. As the gene therapy agent to be injected into the affected tissue, a liposome containing the gene, a cell into which the gene has been introduced, or the like can be used in addition to the vector into which the gene is incorporated.

[0028]

According to the above configuration, the gene therapy agent injection device of the present invention has the following remarkable effects. (1) By cooling the gene therapy agent to a low cooling temperature (for example, about 3 ° C. at a temperature of 25 ° C.), it is possible to maintain its activity for a long period of time, and it is possible to provide the operator with various methods for gene injection. It is possible to relieve the time constraints associated with the work. (2) By automatically controlling the cooling temperature, the injection amount, and the injection rate of the gene therapy agent, a very small amount of the gene therapy agent can be injected into the affected tissue with high precision and high efficiency. (3) Injection of the gene therapy agent into the affected tissue, which differs for each case, can be performed three-dimensionally and effectively, and the amount of the valuable and expensive gene therapy agent used can be minimized. (4) The injection tube and the injection needle, which are expected to be contaminated by the filling of the gene therapy agent, can be injected while washing with a physiological saline or the like under pressure, and the check one-way valve incorporated in the circuit. Minimize the extent of contamination,
Unnecessary infection can be prevented. (5) Preventive measures during and after surgery are simplified, and a safe and reproducible injection of a gene therapy agent is enabled.

[Brief description of the drawings]

FIG. 1 is a schematic view showing one example of a gene therapy drug injection device of the present invention.

FIG. 2 is an enlarged view of an injection tube of the apparatus of FIG.

FIG. 3 is an enlarged view of a syringe pump control device of the device of FIG. 1;

FIG. 4 is an enlarged view of an injection control unit of the device of FIG.

FIG. 5 is an enlarged view of a cooling recirculation device of the device of FIG.

FIG. 6 is an enlarged view of an injection part of the device of FIG.

FIG. 7 is an enlarged view of a syringe of the device of FIG. 1;

FIG. 8 is an enlarged view of the injection needle of the device of FIG. 1;

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 Syringe pump control device 2 Channel switching three-way cock 2a Lock connector for tube connection for rear injection 2b Lock connector for tube connection for front injection 2c One-way valve for non-return prevention 2d Filling port 3 Tube for injection on rear 4 Small Injection syringe 4a Hard piston head 4b Lock connector for connecting piston holder 4c Lock connector for connecting rear injection tube 5 Front injection tube 5a Port for connecting cooling water tube 8a 5b Port for connecting cooling water tube 8b 5c Lock Connector for Injection Needle Connection 6 Ultrasonic Reaction Type Injection Needle 6a Side Hole 6b Lock Connector for Connecting Front Injection Tube 7 Affected Tissue 7a Syringe Holder 7b Piston 7c Piston Holder 8a Cooling Water Recirculation Tube 8b Cooling Water Recirculation Tube 9 Temperature sensor 10 Injection control unit 10a Single injection amount setting button 10b Injection time setting button 10c Injection pressure display unit 10d Injection temperature display unit 11 Cooling recirculation device 11a Temperature setting unit 11b Cooling water storage chamber 11c Flow setting unit 11d Reflux Pump 12 injection unit

Continued on the front page (72) Inventor Tadashi Tadashi Tadashi 169 Toshinda, Okayama City, Okayama Prefecture (72) Inventor Jun Nakagawa 3-6-11 Shimizu-cho, Toyama City, Toyama F-term (reference) 4C060 FF35 4C066 AA09 BB01 CC01 CC10 DD12 EE14 FF04 HH13 KK02 LL30 QQ31 QQ41 QQ94

Claims (6)

[Claims] An apparatus for injecting a gene therapy agent, comprising: means for injecting a gene therapy agent having a cooling means; and a pump control device connected to the injection means. 2. The gene therapy agent injection device according to claim 1, wherein the pump control device is capable of controlling a cooling temperature, an injection amount, and an injection speed of the gene therapy agent. 3. The gene therapy agent according to claim 1, wherein the means for injecting the gene therapy agent is provided with a closed sharpened tip and a metal injection needle having a side hole at the tip. Infusion device. 4. The gene therapy agent injection means has a flexible injection tube connected to an injection needle, and the injection tube is separated into a front injection tube and a rear injection tube by a three-way switching valve. The gene therapy agent injection device according to claim 3, wherein a cooling tube is provided on an outer peripheral portion of the front injection tube. 5. The gene therapeutic agent injection device according to claim 4, wherein a cooling temperature of the gene therapeutic agent is monitored and controlled by a temperature sensor provided in the front injection tube. 6. A check valve is provided at a connection between the front injection tube and the three-way switching valve.
Or the gene therapy agent injection device according to 5.