On January 15, 2009, in Genomics

This is the third of a three-part series that digests voluminous genomics-related articles published in recent months. The first of the series (November issue) covered the accelerating development of genomics technologies and initiatives. The second (December) covered the impact this acceleration is having on genomics understanding. This third issue illustrates the impact our understanding is having in terms of genetic and proteomic therapies for disease.

In light of these advances described in this series, we name Genomic Medicine as our 2008 Health Future of the Year. And in light of the fact that with the publication of this issue Health Futures Digest has completed six full years of publication, we are celebrating with a makeover. The goal is more than cosmetic; we seek to generate your input on the issues we report, by providing the ability to comment directly on the articles and to respond to comments made by other readers. We hope you will make use of it.

Best wishes for 2009. Despite the economic gloom, we believe that the combination of crisis plus a more decent and capable administration spells very good news for the healthcare system and the people it will serve.

–David Ellis and Julian Bond

Progress in Genetic and Proteomic Therapies

January: Tuberous Sclerosis

At the one-year (halfway) point of a clinical trial of the drug sirolimus to treat kidney tumors in tuberous sclerosis patients, the tumors had shrunk by an average of 26 percent. Tuberous sclerosis is an inherited disease that causes tumors to grow in many of the organs of the body.

Sirolimus controls the activity of a protein, mTOR, which is normally controlled by the TSC1 and TSC2 genes. If the genes fail, mTOR becomes overactive and causes the disease.

April and September: Eye Disease

Following injections of material containing millions of copies of a corrective gene beneath the retina, four of six patients with Leber congenital amaurosis (LCA) “showed signs” of “significant” improvement in their vision. Two of the volunteers who could only see hand motions were able to read a few lines of an eye chart within weeks, and could see better in dim light.

The method could be ready for use within two years to treat people suffering from inherited retinal diseases, and within three years it could be ready for clinical trials as a therapy for age related macular degeneration.

May: Head and Neck Cancer

Advexin, a modified adenovirus that expresses the tumor-suppressing gene p53 had remarkable success in phase III clinical trials in end-stage head and neck cancer patients. The p53 gene’s role is to halt the division of a defective cell and then force the cell to kill itself, but cancer cells manage to switch it off.

Patients whose tumors expressed low levels of mutant p53 and who received the biologic (which was injected into the tumor) had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53. The latter were found to be better off taking the chemotherapy drug methotrexate, which gave them a median survival of 5.9 months. Patients treated with Advexin experienced far fewer side effects, such as pneumonia, than those who received methotrexate.

The mutant p53 biomarker can easily be identified using standard lab techniques, which will enable physicians to personalize treatment to their patients.

Advexin is being tested in other cancers in a variety of clinical trials, and work is under way to develop nanoparticles containing p53 and other tumor-suppressing genes for intravenous delivery, since direct injection into a tumor is impossible for cancers that have metastisized. Nanoparticles that deliver another tumor-suppressor, FUS1, are already in phase I clinical trial for non-small cell lung cancer.

June: Batten Disease

Gene therapy to rid defective brain cells of “garbage” appears safe and effective at slowing down Batten disease (late infantile neuronal ceroid lipofuscinosis, a degenerative neurological disorder in children.) A clinical trial found that injecting a harmless gene-bearing virus into the brain, was safe and, on average, significantly slowed the disease’s progression during an 18-month follow-up period.

The therapy, a liquid containing healthy CLN2 genes housed within an adeno-associated virus, was injected into the brains of the patients through six tiny holes drilled through their skulls.

CLN2 produces an enzyme (TTP-1–deficient in Batten disease) which is responsible for ridding waste from neurons. Small organelles called lysosomes become clogged with toxic material, leading to progressive loss of muscle coordination, involuntary twitching, speech and developmental disorders, loss of vision, and death by age 12.

September: Cystic Fibrosis

The experimental drug VX-770 restored function to a defective protein, CFTR, which cause cystic fibrosis. The proteins are rendered defective by a specific mutation of the CF gene. Patients who received 150mg twice a day saw the concentration of salt in their sweat decrease by almost 50 percent and lung function improve by 10 percent.

September: Pancreatic Cancer

Nanoparticles containing a diphtheria toxin gene successfully killed “a number” of pancreatic cancer cells in an in vitro sample. The treatment targets a molecule found in over three-quarters of pancreatic cancer patients, while leaving normal cells alone. Animal trials are being considered.

September: Pain

The first trial of a gene therapy for the management of pain entered early-stage clinical trials. The clinical trial will target cancer patients with localized pain for whom conventional painkillers have proved ineffective or incapacitating. It uses a crippled version of herpes simplex virus (HSV) to deliver the gene for an opiate-like chemical directly to affected nerves, potentially circumventing the debilitating side effects associated with traditional opiate drugs.

HSV’s natural behavior makes it an ideal delivery vehicle: It infects sensory neurons near the skin and travels to a group of cells near the spinal cord, but no farther, allowing precision targeting of the neurons involved in sensing pain.To administer the treatment, a doctor simply injects the virus into the skin at the site of pain. HSV cannot insert its own genes into the patient’s genome, and is incapable of replicating and causing damage.

Other researchers have injected a virus carrying an opioid gene directly into spinal fluid, successfully treating chronic pain in rats. The HSV therapy is far less invasive; however, invasiveness may be necessary for cancer patients, who experience pain throughout the body.

October: Progeria

About 90 percent of patients with Hutchinson-Gilford progeria syndrome, characterized by extremely rapid aging, die by age 13 from fatal heart attacks or strokes. The disease is caused by a single gene mutation which produces a toxic protein that attaches to and distorts the cell nucleus, preventing it from dividing properly.

In studies of mice genetically engineered to carry the progeria gene mutation, a potential therapy prevented and even reversed cardiovascular disease, which develops as arterial cells accumulate the toxic protein, causing plaque buildup that blocks blood flow.

In the study, farnesyltransferase inhibitors (FTIs) were used to restore the shape of the nucleus, thereby preventing the toxic protein from attaching to it. FTIs not only prevented cardiovascular damage in young mice, but also reversed the disease in older animals treated after the onset of arterial damage. These results have the potential to benefit all patients with cardiovascular disease, including the elderly.

FTIs are already being tested for safety and efficacy in progeria patients. It is seen as just one in a variety of strategies needed to combat the disease–others include stem cell and gene therapies.

October: Muscular Dystrophy

Duchenne muscular dystrophy (DMD) patients–predominantly males who will lose the ability to walk by their teens and typically die before the age of 30–have a gene mutation that disrupts the production of a protein (dystrophin) whose absence destroys muscle cells and replaces them with fibrous, bony, or fatty tissue. Tests that screen newborns with a high risk of muscular dystrophy have not been widely used because of the lack of a therapy.

That may change, thanks to a virus-vector delivery method shown to reach every skeletal and cardiac muscle of the body in a canine model. It means that whole body correction of DMD in humans is possible. In an earlier study in mice, the research team demonstrated that heart tissue could be corrected by this therapy sufficient to sustain a healthy life even if only 50 percent of the muscle was protected by the therapy.


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