Gene Therapy for Chronic Pain enters First Human Trial....

Gene therapy for chronic pain enters first human trial

U-M Phase 1 trial will test therapy in cancer patients with intractable pain

Media contact: Katie Vloet
E-mail: kgazella@umich.edu
Tel: 734-764-2220

ANN ARBOR, Mich. -This week, University of Michigan scientists will begin a phase 1 clinical trial for the treatment of cancer-related pain, using a novel gene transfer vector injected into the skin to deliver a pain-relieving gene to the nervous system.

A gene transfer vector is an agent used to carry genes into cells. In this groundbreaking clinical trial, the investigators will use a vector created from herpes simplex virus (HSV) - the virus that causes cold sores - to deliver the gene for enkephalin, one of the body's own natural pain relievers.

"In pre-clinical studies, we have found that HSV-mediated transfer of enkephalin can reduce chronic pain," says David Fink, M.D., Robert Brear Professor and chair of the department of neurology at the U-M Medical School. Fink developed the vector with collaborators and will direct the study.

"After almost two decades of development and more than eight years of studies in animal models of pain, we have reached the point where we are ready to find out whether this approach will be effective in treating patients," Fink says. The investigators are recruiting 12 patients with intractable pain from cancer to examine whether the vector can be used safely to deliver its cargo to sensory nerves.

The trial represents two firsts, says Fink: It is the first human trial of gene therapy for pain, and the first study to test a nonreplicating HSV-based vector to deliver a therapeutic gene to humans. Fink says the technique may hold promise for treating other types of chronic pain, including pain from nerve damage that occurs in many people with diabetes.

The HSV vector, genetically altered so it cannot reproduce, has a distinct advantage, Fink says: "Because HSV naturally travels to nerve cells from the skin, the HSV-based vector can be injected in the skin to target pain pathways in the nervous system."

Gene therapy for pain

Chronic pain is an important clinical problem that, despite a wide array of therapeutic options, cannot be effectively treated in a substantial number of patients. Fink notes that one key problem in treating pain is that the targets of conventional pain-relieving medications tend to be widely distributed in the nervous system, so that "off target" side effects of the drugs often preclude the use of those drugs at fully effective doses.

"This provides the rationale for using gene transfer to treat pain," Fink says. "We use the vector to deliver and express a chemical that breaks down very quickly in the body. The targeted delivery allows us to selectively interrupt the transmission of pain-related signals and thus reduce the perception of pain."

Enkephalin is one member of the family of opioid peptides that are naturally produced in the body. Opioid peptides exert their pain-relieving effects by acting at the same receptor through which morphine and related opiate drugs achieve their pain-relieving effects. In this trial the enkephalin peptide, produced as a result of the gene transfer, will be released selectively in the spinal cord at a site involved in transmitting pain from the affected body part to the brain.
"We hope that this selective targeting will result in pain-relieving effects that cannot be achieved by systemic administration of opiate drugs," Fink says. "This trial is the first step in bringing the therapy into clinical use. A treatment is at least several years off."

Preclinical studies led to human trial

The phase I clinical trial represents the culmination of studies performed by investigators working in the U-M laboratory co-directed by Fink and his wife, Marina Mata, M.D., also a professor of neurology at U-M, along with colleagues at the University of Pittsburgh led by Joseph Glorioso, Ph.D. In published studies, the researchers have demonstrated that HSV-mediated gene transfer is effective in rats with pain resulting from inflammation, nerve damage or spinal cord injury, and in mice with pain caused by cancer. The extensive preclinical data in animal models were reviewed by the Recombinant DNA Advisory Committee at the National Institutes of Health. The Food and Drug Administration approved an investigational new drug application for the therapy in February.

Funding for the preclinical studies was provided by the NIH, and related studies of the vector were funded by grants from the Department of Veterans Affairs and the Juvenile Diabetes Research Foundation. The human trial is supported by a research grant from Diamyd, Inc., a subsidiary of Diamyd Medical (DIAMB.ST), a publicly traded Swedish biotechnology company. Fink has no financial interest in or consulting relationship with Diamyd. He is an inventor on patents related to this work that are owned by the University of Pittsburgh and licensed to Diamyd. Susan Urba, M.D. and Frank Worden, M.D., medical oncologists at the U-M Comprehensive Cancer Center will serve as principal clinicians for the study, assisted by Suzette Walker, N.P., who will serve as study coordinator, and Heidi L'Esperance, who will serve as data manager.

Trial details

The investigators are seeking patients with intractable pain related to cancer that is unresponsive to maximally tolerated doses of conventional analgesic drugs. The vector will be delivered in 10 small injections into the skin, and will require an overnight stay in the Michigan Clinical Research Unit at U-M Hospital. For more information, contact the U-M Cancer AnswerLine, 800-865-1125, or visit:

www.med.umich.edu/engage/
www.cancer.med.umich.edu/research/clinical_trials.shtml
www.med.umich.edu/neurology

Coincidences....Do You Believe In Them?

I had to post this because I was reading a book and this is part of the Introduction. The book is titled "Small Miracles" But I found this Introduction very interesting as well as eye opening. Sometimes we do have these moments in life where we say things like, "It's was just a coincidence", "Wow, what a coincidence that was", or numerous other comments like that. But it's very seldom that we consider the possibility of it being Divine Presence. There are many times in my life where I can look back and say that those 'so called' coincidences where in fact a Divine Presence, can you?

You know, there are moments in life when we catch our breath and glimpse God's presence. Sometimes it is when we see the glowing face of a sleeping child, sometimes it is when we hear a song. These moments, which shine for an instant and then vanish in a flash, convey a sense of the Divine.

Every leaf, every blade of grass bears God's imprint. But these days most of us are urban dwellers leading hectic lives, and have lost the connection to the earth that enriched our forefathers and helped them see God. Obscured by skyscrapers and the haze of polluted skies, we can barely see the stars, let alone sense a Divine Presence.

Living as so many of us do, lives of alienation and despair, how can we help ourselves reconnect; to God, to one another, to our very selves?

Beyond nature, there are teachers, other experiences that can help us along our journey. These guides, beacons of light and signposts in the labyrinthine wilderness in which we wander, offer us gentle instruction and compassionate encouragement as they firmly propel us back to the path from which we may have strayed.

These experiences, common to us all, can help lead us to our unfulfilled destiny. They occur within the great universal flow of energy, and require nothing more that our sheer awareness of their presence. When consciousness is cultivated and perception is heightened, these experiences can serve as vital tokens of growth and transformation. To encounter these moments in their fullness and richness, to be aware of their message and hear their music, is truly to know God. And predominant among these experiences is the phenomenon we call coincidences.

Coincidences have been defined as luck, chance, a fluke, something our of the ordinary, or a random conjoining of inexplicable events that defies our sense of the reasonable. I firmly believe that coincidences are much more than simple accidents or quirks of fate. To me, coincidences are blessings, the spiritual manna that hosts of angels send down to illuminate our path. They are vivid, striking, awe-inspiring examples of Divine Providence. They are acts of God.

Thousands of years ago, God spoke to man through sublime miracles he preformed on massive scales. We are not so fortunate. Today we wrestle with a hidden God, a concealed God, a God who no longer parts seas, stops the sun, or turns people into pillars of salt. Instead we have coincidences. Smaller, more personal, everyday miracles. For when a coincidence does take place, it is nothing more and nothing less than God tapping us on the shoulder, whispering, or at times even shouting: "I'm here! I'm with you!" Coincidences are God's way of remaining anonymous.

Coincidences can also be seen as opportunities for change, vital keys towards expanding our consciousness. If we can learn to become more aware of and attuned to coincidences, more cognizant of their significance, that we will evolve to a higher state of being. When we integrate both the experience and the meaning of coincidences into our lives, we open ourselves to the enriching possibilities, the blessings, and the sense of harmony with the universe that they offer.
I heard a story once of a holy man who radiated an unusual aura of inner peace and joy. An unearthly, almost celestial glow shone from his body, and attracted vast crowds who pursued him everywhere. They would call to him, "Are you a God?" "No." he would answer. "Are you an angel?" "No." "Are you a prophet?" finally he said, "No, I am simply awake."

Coincidences are everywhere and can happen any time. When your soul is ready, they will come. All that is required is that you open your heart.

Pharmaceutical Biotech Scientist Discovers New Molecule to Treat Chronic Pain

08-15-2008


Northeastern University Pharmaceutical Sciences professor and Center for Drug Discovery director Alexandros Makriyannis and a team of researchers have created a synthetic molecule that could be used to treat chronic pain in patients with diseases such as diabetes or shingles.

The findings were published in a recent issue of Psychopharmacology in an article titled “Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog.” The team of researchers involved in this study included Northeastern University Pharmaceutical Sciences researchUniversity of Connecticut. associate professor Torbjorn U.C. Jarbe, as well as Chen Li and Qian Liu, formerly of the

The new molecule, AM1346, mimics, though is more powerful than, anandamide an endogenous cannabinoid neurotransmitter found prominently in the brains of humans and animals. Anandamide is a naturally occurring part of the endocannabinoid system that regulates pain, controls heart rate and blood pressure, and modulates mood and appetite.

In order to test anandamide against AM1346, the researchers studied discriminative behavior in rats and concluded that the animals act in a similar fashion when injected with the two agents. Makriyannis said the rats were trained to respond to an injection of AM1346 by pushing a lever that delivered food to the animals. When trained without exposure to AM1346, an alternate lever produced food. Thus, the presence or absence of the training drug controlled the choice behavior of the animals. Additionally, the cannabinoid antidote rimonabant blocked these drug effects. That is, the animals selected the nondrug associated lever in tests with rimonabant and the other drugs.

“AM1346 is a more potent and stable synthetic compound than anandamide,” Makriyannis said. “It will serve as a test compound to study and understand more completely the endocannabinoid system and could have potential therapeutic implications as a topically applied pain killer,” he said, adding that there is considerable interest from the pharmaceutical industry for researchers to discover new medications within the body’s biochemical system.

For more information on Professor Makriyannis’ research, please contact Jason Kornwitz at 617-373-5729 or j.kornwitz@neu.edu.