New Gene Therapy could help ease Chronic Pain
Posted: Tue Feb 17, 2009 3:44 am
http://www.news8austin.com/content/head ... 81&SecID=2
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New therapy could help ease chronic pain
Updated: 2/16/2009 11:01:21 AM
By: Ivanhoe Broadcast News
What's different about gene therapy for chronic pain?
Dr. Fink: We have a lot of drugs that we use to treat pain, but the problem in using those drugs is that as you raise the dose of the drug to try to control the chronic pain, you run into the problem with side effects that the drug has effects on the nervous system on non-nervous tissue that is unrelated to its effect in blocking pain, but limits your ability to increase the dose to where you'd like to be; and what we decided to do, not probably more than 10 years ago, was that we thought that if we could deliver a substance, a drug, if you will, that would block pain, specifically to the pain pathway, and in the studies that we're doing to the pain pathway at the first junction between the primary pain-sensing neuron, the first pain-sensing neuron and the spinal cord, if we could deliver these drugs to that site using gene-transfer, we could block pain without the side effects you get when you try to use those same substances by systemic administration.
How do you find those specific points?
Dr. Fink: The pain neurons go from the skin into the spinal cord, and they do that in segmental fashion so you know what level you're at, and the beauty of the gene transfer system that we've developed is that we use a gene transfer vector -- that is, a vehicle that we've designed to deliver genes into nerve cells -- and we created our vector out of a modified herpes-simplex virus because herpes simplex, of its own accord, goes from the skin into the neurons that we want to target, and we crippled the virus so that it's otherwise inert, and that's what makes it into a vector.
Is it like a train taking it where it needs to go?
Dr. Fink: That's right. It's a shuttle. It is a shuttle that goes from one place, from the skin, into the sensory neuron. When you inject it into the skin, it goes into the sensory neuron that's right next to the spinal cord, and that's what it does, and it stays there.
Does this vector only transport a certain kind of pain medicine?
Dr. Fink: We have made, actually, a series of these vectors. The vector is like a shuttle, and we can put into that shuttle. We can put any one of a number of different genes, and we have; but for the trial that we're doing, we put into this vector the gene-coding for the peptide for the substance inkephalin, and that's one of the natural substances that binds to the receptors that morphine bonds to. What makes morphine effective, and why it's been used as a pain medicine for thousands of years, is that it binds to receptors that are present already in the body -- but they weren't there for morphine. They were there because your body makes substances like inkephalin, so we're delivering what we would term technically an indigenous opioid peptide.
What types of pain does this help?
Dr. Fink: We have examined in animal studies the effect of this type of gene transfer in models of inflammatory pain. That's pain that occurs when you have inflammation in a joint, or that would occur with a tissue injury, in neuropathic pain that happens when you have nerve damage, in pain caused by cancer in bone. Other people have looked at pain caused by inflammation of internal organs such as the pancreas or pain of the face, so many different types of pain, and with different genes that we transfer; but for this first human trial -- because this will be the first human trial of this type of therapy -- we've targeted, and gotten approval from the Food and Drug Administration, to test this gene transfer in patients who have terminal cancer and who have intractable pain from that cancer, this pain that's unresponsive to the highest dosages of opiate drugs that they can tolerate.
Will this target people with certain kinds of cancer?
Dr. Fink: No. Patients who are eligible for this trial are patients with any type of cancer who have intractable pain.
How do you deliver this therapy?
Dr. Fink: For patients who have this type of pain -- and they would have to have a focal pain -- this is not a treatment for pain all over the body. We will inject the vector in a series of ten very small injections right into the skin, in the region of skin that corresponds to the distribution of the pain, of where the pain would radiate.
How long would it take to work?
Dr. Fink: I have to make it clear that this is what is termed by the FDA as a phase 1 trial, so this is a true safety and dose-finding trial. We do have secondary outcome measures of potential pain relief, but with enrolling only three patients at each dose of the injection, and with no placebo control, we won't really be able to say anything from this trial about whether it relieves pain, but what we will be able to say is that it is safe, and then we can go on to a trial to test that. What I can tell you is that in the animal experiments, pain relief usually begins within several days, and with the particular construct that we're using, the pain relief is maximal at about one week and lasts about four to six weeks and that we have other constructs where we can have prolonged expressions of the gene product, and then have pain relief that goes on for months at a time; but for this first trial, one of the safety features of this vector approach is that it shuts off by itself.
Is this the first type of gene therapy for chronic pain?
Dr. Fink: Yes. This is the first human trial of gene therapy for pain.
What's exciting about this?
Dr. Fink: I've spent the last 20 years working on modifying herpes viruses and using them as vectors to develop treatments for diseases. I am a neurologist, and I am interested in developing novel treatments for diseases of the nervous system, and we've spent almost the last 20 years working on the development of these herpes vectors and testing them in models of neurologic disease, where that type of targeted delivery of a short-acting gene product to a particular place in the nervous system would be particularly desirable; and we have a lot of evidence, in models of neuropathy, where nerve degeneration -- a disease that right now, there is essentially no treatment for -- and in models of pain, and so this is the first step into people. If we prove that this is safe, then we have other vectors for particular types of pain that are actually untreatable, and we have vectors that would use the same technology that we could apply for to prevent nerve damage that you see, for instance, in diabetes or with high doses of chemotherapeutic agents. So if it works, it will be really exciting.
So like radiation, this kind of treatment is becoming more targeted?
Dr. Fink: That's right. This is a particular type of targeted treatment, and I think it's conceptually actually relatively simple, and the virus has actually solved many of the problems for us. So it's not particularly high-tech in some ways, but on the other hand, if it actually works in people, it would be really exciting.
How soon will this treatment be available?
Dr. Fink: We expect to complete this trial within a year, and we've already begun planning for the phase II trial to determine whether it's effective, so I think in terms of far off, it all depends on your time frame.
This is the first use, and that's another thing, actually, which makes it exciting. This is the first time that anyone is using a recombinant herpes-based vector to deliver a foreign gene into the body. I will say that herpes viruses have been used as therapeutic agents. People have made herpes viruses that are not inert like our vectors, but that are slightly compromised, so that they have different replication characteristic, and use them. They call them oncolytic, because when they inject into tumors, they divide into the tumors and kill the tumor cells. So those types of viruses -- and those type of herpes viruses have been injected into tumors in the breast and brain in more than 250 patients without any problems -- so we have confidence that this is safe; but those viruses, those oncolytic herpes viruses, don't carry foreign genes, so this is the first gene therapy for pain, and it's the first use of herpes virus to deliver a foreign gene being tested in people.
What gave you the idea to use the herpes virus as a vector?
Dr. Fink: That was a complete accident. I happened to be in the lab one day, back in 1989, and Joe Glorioso, who was really a groundbreaking herpes virologist who at that time was an assistant dean here in Michigan, was doing a tour of the laboratory space, and my studies at that time were focused on the retro-grade axonal transport -- how substances move from nerve terminals back towards the cell body -- and he was walking through the hall, and we started to chat, and he said, "I study herpes viruses and they move by retrograde transfer. We should talk." We started talking, and we haven't stopped.
David Fink, MD
University of Michigan Medical Center
Ann Arbor, MI
(734) 936-9020
http://www.med.umich.edu
=======================================================
New therapy could help ease chronic pain
Updated: 2/16/2009 11:01:21 AM
By: Ivanhoe Broadcast News
What's different about gene therapy for chronic pain?
Dr. Fink: We have a lot of drugs that we use to treat pain, but the problem in using those drugs is that as you raise the dose of the drug to try to control the chronic pain, you run into the problem with side effects that the drug has effects on the nervous system on non-nervous tissue that is unrelated to its effect in blocking pain, but limits your ability to increase the dose to where you'd like to be; and what we decided to do, not probably more than 10 years ago, was that we thought that if we could deliver a substance, a drug, if you will, that would block pain, specifically to the pain pathway, and in the studies that we're doing to the pain pathway at the first junction between the primary pain-sensing neuron, the first pain-sensing neuron and the spinal cord, if we could deliver these drugs to that site using gene-transfer, we could block pain without the side effects you get when you try to use those same substances by systemic administration.
How do you find those specific points?
Dr. Fink: The pain neurons go from the skin into the spinal cord, and they do that in segmental fashion so you know what level you're at, and the beauty of the gene transfer system that we've developed is that we use a gene transfer vector -- that is, a vehicle that we've designed to deliver genes into nerve cells -- and we created our vector out of a modified herpes-simplex virus because herpes simplex, of its own accord, goes from the skin into the neurons that we want to target, and we crippled the virus so that it's otherwise inert, and that's what makes it into a vector.
Is it like a train taking it where it needs to go?
Dr. Fink: That's right. It's a shuttle. It is a shuttle that goes from one place, from the skin, into the sensory neuron. When you inject it into the skin, it goes into the sensory neuron that's right next to the spinal cord, and that's what it does, and it stays there.
Does this vector only transport a certain kind of pain medicine?
Dr. Fink: We have made, actually, a series of these vectors. The vector is like a shuttle, and we can put into that shuttle. We can put any one of a number of different genes, and we have; but for the trial that we're doing, we put into this vector the gene-coding for the peptide for the substance inkephalin, and that's one of the natural substances that binds to the receptors that morphine bonds to. What makes morphine effective, and why it's been used as a pain medicine for thousands of years, is that it binds to receptors that are present already in the body -- but they weren't there for morphine. They were there because your body makes substances like inkephalin, so we're delivering what we would term technically an indigenous opioid peptide.
What types of pain does this help?
Dr. Fink: We have examined in animal studies the effect of this type of gene transfer in models of inflammatory pain. That's pain that occurs when you have inflammation in a joint, or that would occur with a tissue injury, in neuropathic pain that happens when you have nerve damage, in pain caused by cancer in bone. Other people have looked at pain caused by inflammation of internal organs such as the pancreas or pain of the face, so many different types of pain, and with different genes that we transfer; but for this first human trial -- because this will be the first human trial of this type of therapy -- we've targeted, and gotten approval from the Food and Drug Administration, to test this gene transfer in patients who have terminal cancer and who have intractable pain from that cancer, this pain that's unresponsive to the highest dosages of opiate drugs that they can tolerate.
Will this target people with certain kinds of cancer?
Dr. Fink: No. Patients who are eligible for this trial are patients with any type of cancer who have intractable pain.
How do you deliver this therapy?
Dr. Fink: For patients who have this type of pain -- and they would have to have a focal pain -- this is not a treatment for pain all over the body. We will inject the vector in a series of ten very small injections right into the skin, in the region of skin that corresponds to the distribution of the pain, of where the pain would radiate.
How long would it take to work?
Dr. Fink: I have to make it clear that this is what is termed by the FDA as a phase 1 trial, so this is a true safety and dose-finding trial. We do have secondary outcome measures of potential pain relief, but with enrolling only three patients at each dose of the injection, and with no placebo control, we won't really be able to say anything from this trial about whether it relieves pain, but what we will be able to say is that it is safe, and then we can go on to a trial to test that. What I can tell you is that in the animal experiments, pain relief usually begins within several days, and with the particular construct that we're using, the pain relief is maximal at about one week and lasts about four to six weeks and that we have other constructs where we can have prolonged expressions of the gene product, and then have pain relief that goes on for months at a time; but for this first trial, one of the safety features of this vector approach is that it shuts off by itself.
Is this the first type of gene therapy for chronic pain?
Dr. Fink: Yes. This is the first human trial of gene therapy for pain.
What's exciting about this?
Dr. Fink: I've spent the last 20 years working on modifying herpes viruses and using them as vectors to develop treatments for diseases. I am a neurologist, and I am interested in developing novel treatments for diseases of the nervous system, and we've spent almost the last 20 years working on the development of these herpes vectors and testing them in models of neurologic disease, where that type of targeted delivery of a short-acting gene product to a particular place in the nervous system would be particularly desirable; and we have a lot of evidence, in models of neuropathy, where nerve degeneration -- a disease that right now, there is essentially no treatment for -- and in models of pain, and so this is the first step into people. If we prove that this is safe, then we have other vectors for particular types of pain that are actually untreatable, and we have vectors that would use the same technology that we could apply for to prevent nerve damage that you see, for instance, in diabetes or with high doses of chemotherapeutic agents. So if it works, it will be really exciting.
So like radiation, this kind of treatment is becoming more targeted?
Dr. Fink: That's right. This is a particular type of targeted treatment, and I think it's conceptually actually relatively simple, and the virus has actually solved many of the problems for us. So it's not particularly high-tech in some ways, but on the other hand, if it actually works in people, it would be really exciting.
How soon will this treatment be available?
Dr. Fink: We expect to complete this trial within a year, and we've already begun planning for the phase II trial to determine whether it's effective, so I think in terms of far off, it all depends on your time frame.
This is the first use, and that's another thing, actually, which makes it exciting. This is the first time that anyone is using a recombinant herpes-based vector to deliver a foreign gene into the body. I will say that herpes viruses have been used as therapeutic agents. People have made herpes viruses that are not inert like our vectors, but that are slightly compromised, so that they have different replication characteristic, and use them. They call them oncolytic, because when they inject into tumors, they divide into the tumors and kill the tumor cells. So those types of viruses -- and those type of herpes viruses have been injected into tumors in the breast and brain in more than 250 patients without any problems -- so we have confidence that this is safe; but those viruses, those oncolytic herpes viruses, don't carry foreign genes, so this is the first gene therapy for pain, and it's the first use of herpes virus to deliver a foreign gene being tested in people.
What gave you the idea to use the herpes virus as a vector?
Dr. Fink: That was a complete accident. I happened to be in the lab one day, back in 1989, and Joe Glorioso, who was really a groundbreaking herpes virologist who at that time was an assistant dean here in Michigan, was doing a tour of the laboratory space, and my studies at that time were focused on the retro-grade axonal transport -- how substances move from nerve terminals back towards the cell body -- and he was walking through the hall, and we started to chat, and he said, "I study herpes viruses and they move by retrograde transfer. We should talk." We started talking, and we haven't stopped.
David Fink, MD
University of Michigan Medical Center
Ann Arbor, MI
(734) 936-9020
http://www.med.umich.edu