VM202 Yet More Information About The Promising Gene Therapy For Neuropathy

Today's post from the always excellent sciencedaily.com (see link below) is another article about VM202 - (that unattractively-named, new non-viral gene therapy we've mentioned a couple of times in the last 2 weeks). The difference here is that it is relatively easy for the casual reader to understand and certainly seems to be something to start becoming cautiously excited about. Remember too, that just because the title includes the word 'diabetics' doesn't mean that it doesn't apply to most other forms of neuropathy too.

Neuropathy: Relief for diabetics with painful condition
Date:March 5, 2015 Source: Northwestern University 

Summary:

Those with painful diabetic neuropathy who received two low dose rounds of a non-viral gene therapy called VM202 had significant improvement of their pain that lasted for months, researchers report. "Right now there is no medication that can reverse neuropathy," the study's first author said. "Our goal is to develop a treatment. If we can show with more patients that this is a very real phenomenon, then we can show we have not only improved the symptoms of the disease, namely the pain, but we have actually improved function."

Walking barefoot on sand "felt like walking on glass" for Keith Wenckowski, who has lived with type-one diabetes for more than two decades.

One of the participants in a new Northwestern Medicine study who suffered from painful diabetic neuropathy (PDN), Wenckowski finally found relief from the constant foot pain that required him to wear shoes at all times, even to the beach.

The study found that those with PDN who received two low dose rounds of a non-viral gene therapy called VM202 had significant improvement of their pain that lasted for months.

"I can now go to a beach and walk on the sand without feeling like I am walking on glass," Wenckowski said.

The results of this phase two, double-blind, placebo-controlled study will be published March 5 in the journal Annals of Clinical and Translation Neurology.

Right now there is no treatment for this disease of the peripheral nerves that affects 20 to 25 percent of diabetics. Patients with the most extreme form of the disease feel intense pain with a slight graze or touch. The pain can interfere with daily activities, sleep, mood and can diminish quality of life.

"Those who received the therapy reported more than a 50 percent reduction in their symptoms and virtually no side effects," said Dr. Jack Kessler, lead author of the study. "Not only did it improve their pain, it also improved their ability to perceive a very, very light touch."

Kessler is the Ken and Ruth Davee Professor of Stem Cell Biology in the department of neurology and a professor in the department of pharmacology at Northwestern University Feinberg School of Medicine. He also is an attending physician at Northwestern Memorial Hospital.

VM202 contains human hepatocyte growth factor (HGF) gene. Growth factor is a naturally occurring protein in the body that acts on cells -- in this case nerve cells -- to keep them alive, healthy and functioning. Future study is needed to investigate if the therapy can actually regenerate damaged nerves, reversing the neuropathy.

Wenckowski had continuous numbness, but now, more than a year since he received the therapy, his symptoms have not returned. "I am hoping the effects I am feeling do not cease," he said.

Patients with painful diabetic neuropathy have abnormally high levels of glucose in their blood. These high levels of glucose can be toxic.

Damaged nerve cells send out abnormal signals, causing the patients to feel pain, usually in their lower limbs and fingertips. The condition can lead to injuries, chronic foot ulcers and even amputations.

Painkillers and other medications can alleviate symptoms, but those drugs often come with undesirable side effects.

"We are hoping that the treatment will increase the local production of hepatocyte growth factor to help regenerate nerves and grow new blood vessels and therefore reduce the pain," said Dr. Senda Ajroud-Driss, associate professor in neurology at Feinberg, an attending physician at Northwestern Memorial Hospital and an author of the study.

Eighty-four subjects with PDN completed this study. They went to a clinic twice in a two-week timespan for a series of injections into the back of their calf muscles and lower legs. Some received injections of a saline placebo, others a low dose of the therapy and others a higher dose.

"We found that the patients who received the low dose had a better reduction in pain than the people who received the high dose or the placebo," Ajroud-Driss said. "Side effects were limited to injection site reaction."

The subjects reported their pain symptoms to the researchers over the next nine months. At three months, patients in the low-dose group experienced a significant reduction in pain compared to the placebo group. The effect persisted at six and nine months in the low-dose group, the scientists said.

A future, much larger phase three study will soon be underway.

"Right now there is no medication that can reverse neuropathy," Kessler said. "Our goal is to develop a treatment. If we can show with more patients that this is a very real phenomenon, then we can show we have not only improved the symptoms of the disease, namely the pain, but we have actually improved function."

Story Source:

The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.

Journal Reference:
John A. Kessler, A. Gordon Smith, Bong-Soo Cha, Sung Hee Choi, James Wymer, Aziz Shaibani, Senda Ajroud-Driss. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Annals of Clinical and Translational Neurology, 2015; DOI: 10.1002/acn3.186

http://www.sciencedaily.com/releases/2015/03/150305110534.htm

BALDNESS HUMAN HAIRLESS GENE IDENTIFIED

It's not a hair-brained idea: A new research report appearing in the April 2014 issue of The FASEB Journal explains why people with a rare balding condition called "atrichia with papular lesions" lose their hair, and it identifies a strategy for reversing this hair loss. Specifically the report shows for the first time that the "human hairless gene" imparts an essential role in hair biology by regulating a subset of other hair genes. This newly discovered molecular function likely explains why mutations in the hairless gene contribute to the pathogenesis of atrichia with papular lesions. In addition, this gene also has also been shown to function as a tumor suppressor gene in the skin, raising hope for developing new approaches in the treatment of skin disorders and/or some cancers

Identification of hairless as a histone demethylase may shed new insights into its mechanism of action in regulating skin and hair disorders," said Angela M. Christiano, Ph.D., FACMG, a researcher involved in the work from the Departments of Dermatology and Genetics and Development at the Columbia University College of Physicians and Surgeons in New York, NY. "The genes identified in this study could open up new opportunities for developing mechanism-driven approaches for future prevention or treatment of skin diseases including skin cancer and rare forms of hair loss."

To make their discovery, Christiano and colleagues defined the histone demethylase function of the human hairless gene, both in vitro and using cultured human cells. When the hairless protein was mixed with specific histone substrates under defined reaction conditions, the hairless protein causes a reduction in the level of methylation modification of the histone substrates. Similarly, upon expression of normal hairless protein, but not a mutant form of the hairless protein, researchers observed a drastic loss of histone methylation in human cells. This suggests that this may be the "on/off" switch for hair growth as well as a promising target for some types of skin disease.

"Humans have tried everything to keep their hair, from snake oils to spray-on bald spot solutions," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Now, however, we are finally getting to the root of the problem to manipulate one of the switches that control hair growth."

The HCN2 gene and Neuropathy

You will frequently see 'gene therapy' named as one of the three, proven, effective therapies for treating neuropathy (the others being capsaicin and cannabis - see right for other posts on these). However, gene therapy is not yet approved by the major international health organisations; is largely experimental; remains the subject of ongoing studies and for the ordinary reader, is almost impossible to understand because of its scientific complexity. This article from ScienceDaily.com (see link below) tries to explain the reasoning behind it as simply as possible and gives some idea of how it works for the non-medical reader. It is probably the best chance we have for a universally accepted treatment in the future so its progress may be worth following.

Gene That Controls Chronic Pain Identified
ScienceDaily (Sep. 9, 2011)

A gene responsible for regulating chronic pain, called HCN2, has been identified by scientists at the University of Cambridge. The research, published September 9 in the journal Science, opens up the possibility of targeting drugs to block the protein produced by the gene in order to combat chronic pain.

Approximately one person in seven in the UK suffers from chronic, or long-lasting, pain of some kind, the commonest being arthritis, back pain and headaches. Chronic pain comes in two main varieties. The first, inflammatory pain, occurs when a persistent injury (e.g. a burn or arthritis) results in an enhanced sensitivity of pain-sensitive nerve endings, thus increasing the sensation of pain.

More intractable is a second variety of chronic pain, neuropathic pain, in which nerve damage causes on-going pain and a hypersensitivity to stimuli. Neuropathic pain, which is often lifelong, is a surprisingly common condition and is poorly treated by current drugs. Neuropathic pain is seen in patients with diabetes (affecting 3.7m patients in Europe, USA and Japan) and as a painful after-effect of shingles, as well as often being a consequence of cancer chemotherapy. Neuropathic pain is also a common component of lower back pain and other chronic painful conditions.

Professor Peter McNaughton, lead author of the study and Head of the Department of Pharmacology at the University of Cambridge, said: "Individuals suffering from neuropathic pain often have little or no respite because of the lack of effective medications. Our research lays the groundwork for the development of new drugs to treat chronic pain by blocking HCN2."

The HCN2 gene, which is expressed in pain-sensitive nerve endings, has been known for several years, but its role in regulating pain was not understood. Because a related gene, HCN4, plays a critical role in controlling the frequency of electrical activity in the heart, the scientists suspected that HCN2 might in a similar way regulate the frequency of electrical activity in pain-sensitive nerves.

For the study, the researchers engineered the removal of the HCN2 gene from pain-sensitive nerves. They then carried out studies using electrical stimuli on these nerves in cell cultures to determine how their properties were altered by the removal of HCN2.

Following promising results from the in vitro studies in cell cultures, the researchers studied genetically modified mice in which the HCN2 gene had been deleted. By measuring the speed the mice withdrew from different types of painful stimuli, the scientists were able to determine that deleting the HCN2 gene abolished neuropathic pain. Interestingly, they found that deleting HCN2 does not affect normal acute pain (the type of pain produced by a sudden injury- such as biting one's tongue).

Professor McNaughton added: "Many genes play a critical role in pain sensation, but in most cases interfering with them simply abolishes all pain, or even all sensation. What is exciting about the work on the HCN2 gene is that removing it -- or blocking it pharmacologically- eliminates neuropathic pain without affecting normal acute pain. This finding could be very valuable clinically because normal pain sensation is essential for avoiding accidental damage."

This is Biotechnology and Biological Sciences Research Council (BBSRC) and EU funded research.

http://www.sciencedaily.com/releases/2011/09/110908145101.htm

HOW GENE EXPRESSION AFFECTS FACIAL EXPRESSIONS

A person's face is the first thing that others see, and much remains unknown about how it forms -- or malforms -- during early development. Recently, Chong Pyo Choe, a senior postdoctoral fellow working in the lab of USC stem cell researcher Gage Crump, has begun to unwind these mysteries.

In a study published in the journal Development, Choe and Crump describe how a mutation in a gene called TBX1 causes the facial and other deformities associated with DiGeorge syndrome.

During prenatal development, a series of segments form that eventually organize many features of the face. These segments, or "pouches," are composed of a type of specialized tissue called epithelium, which also forms the skin, glands and linings of organs such as the lungs, heart and intestines.

In mice and zebrafish with TBX1 mutations, these pouches never properly develop and the face is deformed, mimicking the severe facial defects typical of DiGeorge syndrome.

By using sophisticated time-lapse imaging, Crump and Choe observed how this happens in both normal and abnormal development. TBX1 works by activating additional genes, including one called Fgf8a that attracts pouch-forming cells to move to the correct locations. This enables the growing pouches to take shape.

"Whereas it has been recognized that mutations in TBX1 underlie DiGeorge syndrome in patients, our study reveals how this master control gene works to organize the complex cellular rearrangements that build the face," said Crump, associate professor and principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.

Gene Found Thats Responsible For Sensing Pain

Today's post from sciencedaily.com (see link below) is actually another step in the current progress of gene therapy towards handling extreme pain. In this case, researchers have identified a gene that blocks pain-sensing nerve cells in a tiny minority of people who cannot feel pain. The emphasis has always been on researching those cells that do transmit pain signals but this could be equally important in leading to ways of genetically blocking selected pain signals in the future. It's a complex subject but this article explains it quite simply and gives us hope that scientists really are on the verge of major breakthroughs when it comes to treating neuropathic chronic pain.

'Pain sensing' gene discovery could help in development of new methods of pain relief 
May 25, 2015 University of Cambridge

A gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the University of Cambridge. The discovery, reported in the journal Nature Genetics, could have implications for the development of new methods of pain relief.

Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals -- around one in a million people in the UK -- are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.

Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.

The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo -- they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their 'master state', which enables them to develop into almost any type of cell in the body).

PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene's function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.

"The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception," says Professor Geoff Woods from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. "Both are equally important to the development of new pain treatments -- if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain."

PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials.

"We are very hopeful that this new gene could be an excellent candidate for drug development, particularly given recent successes with drugs targeting chromatin regulators in human disease," adds Dr Ya-Chun Chen from the University of Cambridge, the study's first author. "This could potentially benefit those who are at danger from lack of pain perception and help in the development of new treatments for pain relief."

Story Source:

The above story is based on materials provided by University of Cambridge. Note: Materials may be edited for content and length.

Journal Reference:
Jan Senderek et al. Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics, May 2015 DOI: 10.1038/ng.3308

http://www.sciencedaily.com/releases/2015/05/150525120428.htm

VM202 More Gene Therapy Evidence For Neuropathy

We've mentioned the subject of today's post from endocrinologyadvisor.com (see link below) several times already but this article explains this exciting new development in terms that almost everybody can understand. Certainly worth talking over with your doctor or specialist and maybe even getting your name onto some trial lists in your area (you may have to fight for that one). However, the idea of 8 injections per year taking away most of our pain, is a very attractive one - let's hope this is a development with real substance. Well worth a read.

Can Gene Therapy Reverse Diabetic Neuropathy?
John Schieszer, MA July 24, 2015 

  A nonviral gene therapy may relieve symptoms of painful diabetic neuropathy.

Gene therapy in the form of a plasmid containing two human hepatocyte growth factor isoforms administered via intramuscular injection may alleviate symptoms and improve quality of life in patients with painful diabetic neuropathy.

In addition, the plasmid —VM202 — may be particularly beneficial in those patients not taking gabapentin or pregabalin, according to researchers at Northwestern University.

In a recently completed double-blind, placebo-controlled study, 84 patients were randomly assigned to receive injections of 8 mg or 16 mg of VM202 per leg (calf muscles and lower leg) or placebo, with doses administered on days 0 and 14.

At 3 months, patients in the low-dose group experienced a significant reduction in pain compared with the placebo group, the researchers found.1

“I am very excited about it. This is an enormous problem, and it has a huge impact on people's lives. [These patients] spend so much time in agony,” said study investigator Jack Kessler, MD, who is a professor in the department of neurology at Northwestern University Feinberg School of Medicine in Chicago.

“The data are very, very strong. One issue that remains to be resolved is if we are modifying the disease, and at this time, the jury is still out. In our last study, we had some improvement in patients to feel light stimuli, but we need additional data to say we are altering the course of the disease. If our phase 3 study gives us the same results, then this treatment will be the best option for treating diabetic neuropathy.”

Study Results

The primary outcome for this current study was change in the mean pain score measured by a 7-day pain diary. The analysis also included quality of life and pain measures, and measurement of intraepidermal nerve fiber density, according to Kessler.

The study showed that patients receiving 8 mg of VM202 per leg improved the most in all efficacy measures, including a significant reduction at 3 months in the mean pain score. The reductions in pain continued but were not statistically significant at 6 and 9 months.

“We would probably inject patients four times a year. If it turns out that we are actually making the neuropathy better, then it is reason to think patients would graduate from this, but if it turns out we are just treating the symptoms and not the disease, then we would see injecting the patients four times a year,” Kessler said in an interview with Endocrinology Advisor.

The mean age of the patients in this study was 60 years (approximately 75% men), and the mean duration of diabetes was 15 to 16 years.

The researchers found that 48% of the patients experienced at least a 50% reduction in pain in the treated group compared with 17% in the placebo group. The study also demonstrated significant improvements in the brief pain inventory and the questionnaire portion of the Michigan Neuropathy Screening Instrument.

The researchers noted that the largest reductions in pain were found among patients not on pregabalin or gabapentin.

There were no significant adverse events attributable to VM202 and this treatment was deemed safe and well tolerated. 

More to Learn

It is hoped that VM202, which contains a human hepatocyte growth factor gene, will increase the local production of hepatocyte growth factor to help regenerate nerves and grow new blood vessels and subsequently reduce the pain.

“We believe we are getting a two-for-one treatment. We are supplying nourishment to the nerves, but we are also helping to improve blood vessel function,” said Kessler. “The most remarkable thing is that we pushed the dose up and we had literally not one serious side effect in the entire trial, only [injection] site soreness.”

A large trial is now planned, and the researchers hope to enroll 475 patients at 20 sites across the United States starting in December.

Amanda Peltier, MD, who is an assistant professor of neurology at Vanderbilt University in Nashville, Tennessee, said these study findings are interesting, and this approach could represent a new way of treating diabetic neuropathy with fewer treatment-related adverse effects.

“There is a huge unmet need for diabetic neuropathy as the current medicines have side effects and do nothing to improve or retard the progression of the underlying neuropathy, only treat the pain. In addition, our understanding of diabetic neuropathy has improved for type 1 diabetes, but there has been little headway in improving neuropathy for patients with type 2 diabetes,” Peltier told Endocrinology Advisor.
Looking Ahead

According to M. Sue Kirkman, MD, who is a clinical professor of medicine and the medical director of the Diabetes Care Center Clinical Trials Unit at the University of North Carolina School of Medicine in Chapel Hill, this is a quality of life issue.

Although there are several medications that may help symptoms, they are not effective in all patients and may come with significant side effects, Kirkman said.

“This trial showed promising results, but was relatively small and short-term. Larger and longer-term trials will be important to see if the benefits pan out, and also to get a better feel for potential adverse events. Up to now, treatments for diabetic neuropathy have been purely palliative, with no interventions that seem capable of actually improving nerve function,” Kirkman told Endocrinology Advisor.

“There are some hints from this study that this agent could actually improve nerve function. If that pans out in larger trials, it would be very exciting, since lack of feeling in the feet from advanced diabetic neuropathy is a risk factor for foot ulcers and amputations.”
Reference
Kessler JA et al. Ann Clin Transl Neurol. 2015;2(5):465-478.

http://www.endocrinologyadvisor.com/diabetes/painful-diabetic-neuropathy-gene-therapy/article/428342/