Gene therapy for type 1 diabetes

Type 1 diabetes is a chronic disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose. A gene therapy approach can lead to the long-term survival of functional beta cells as well as normal blood glucose levels for an extended period of time in mice with diabetes. The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells.

A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy. Approximately 9% of the world's adult population has diabetes, which can cause serious health problems such as heart disease, nerve damage, eye problems, and kidney disease.

One fundamental goal of diabetes treatment is to preserve and restore functional beta cells, thereby replenishing levels of a hormone called insulin, which moves blood glucose into cells to fuel their energy needs. But in patients with type 1 diabetes, beta-cell replacement therapy is likely doomed to failure because the new cells might fall victim to the same autoimmunity that destroyed the original cells.

A potential solution to this problem is to reprogram other cell types into functional beta-like cells, which can produce insulin but are distinct from beta cells and therefore are not recognized or attacked by the immune system. To explore the feasibility of this approach, Gittes and first author Xiangwei Xiao of the University of Pittsburgh School of Medicine engineered an AAV vector to deliver to the mouse pancreas proteins called Pdx1 and MafA, which support beta cell maturation, proliferation, and function.

The goal was to generate functional beta-like cells from pancreatic alpha cells, which may be the ideal source for beta cell replacement. For example, alpha cells are plentiful, resemble beta cells, and are in the correct location, all of which could facilitate reprogramming.

By comparing the gene expression patterns of normal beta cells and insulin-producing cells derived from alpha cells, the researchers confirmed nearly complete cellular reprogramming. This gene therapy approach restored normal blood glucose levels in diabetic mice for an extended period of time, typically around four months, and the new insulin-producing cells derived almost exclusively from alpha cells. Moreover, the strategy successfully generated functional insulin-producing cells from human alpha cells.

The viral gene therapy appears to create these new insulin-producing cells that are relatively resistant to an autoimmune attack. This resistance appears to be due to the fact that these new cells are slightly different from normal insulin cells, but not so different that they do not function well. Several features of this approach could facilitate translation to humans. For one, AAV vectors like those used in this study are currently undergoing various gene therapy trials in humans.

Moreover, the viral vectors can be delivered directly to the human pancreas through a routinely performed non-surgical endoscopic procedure; however, this procedure can elicit pancreatic inflammation. In addition, no immunosuppression is required, so patients would avoid related side effects such as an increased risk of infection. However, one major concern was that the mice did eventually return to the diabetic state, suggesting that this treatment would not represent a definitive cure for the disease.
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Gene therapy may kill HIV

Gene therapy may have the potential to eradicate HIV in people infected with the virus, new animal research suggests. The science centers around the use of "chimeric antigen receptor" (CAR) genes. In laboratory work with monkeys, these engineered cells have destroyed HIV-infected cells for more than two years, scientists reported.

T-cells are the cells that are largely responsible for human ability to fight off pathogens and get rid of infections in the body. Every T-cell has a unique receptor, or molecule, on it. That receptor allows the cell to recognize a specific target-a bacteria, or fungus or virus. And when it recognizes that target, it's called into duty to clear it from the body. Taking artificial receptors- CAR that can go on to these cells and allow them to recognize what we want them to recognize," he noted. "In this case that's HIV."

First, the team genetically engineered CAR to find and bind to simian/human immunodeficiency virus (SHIV), a lab-engineered HIV hybrid composed of human virus and monkey virus. Then the researchers modified the DNA of certain blood-forming stem cells so they would carry SHIV-killing CAR. The resulting cells were introduced into the bloodstream of four male juvenile SHIV-infected macaque monkeys.

The engineered cells successfully took up residence in each monkey's bone marrow. The cells moved widely throughout the body, targeting and killing SHIV-infected cells, without producing any notable adverse side effects. The advantage of the stem cell-based approach is that once these cells are grafted into the body, they continuously produce new T-cells that have this gene in them that can target HIV cells.

Plans are underway for a human trial, this study shows both that these cells will respond to HIV and that it's safe. This strategy is unlikely to fully work on its own, CAR will most likely need to be used with antiretroviral therapy. CAR therapy is already leading to impressive results in cancer and holds promise for HIV eradication.
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Gene therapy can destroy HIV infected cells

Through gene therapy, researchers engineered blood-forming stem cells (hematopoietic stem/progenitor cells, or HSPCs) to carry chimeric antigen receptor (CAR) genes to make cells that can detect and destroy HIV-infected cells. These engineered cells not only destroyed the infected cells, they persisted for more than two years, suggesting the potential to create long-term immunity from the virus that causes AIDS.

Antiviral drugs can suppress the amount of HIV in the body to nearly undetectable levels, but only an effective immune response can eradicate the virus. Researchers have been seeking a way to improve the body's ability to combat the virus by engineering blood-forming stem cells to specifically target and kill HIV-infected cells for the life of the individual.

 Although chimeric antigen receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer -- and show promise in treating HIV-1 infection -- the therapy may not impart long-lasting immunity. Researchers, physicians and patients need T cell-based products that can respond to malignant or infected cells that may reappear months or years after treatment.

Because HIV uses CD4 to infect cells, the researchers used a CAR molecule that hijacks the essential interaction between HIV and the cell surface molecule CD4 to make stem cell-derived T-cells target infected cells. When the CD4 on the CAR molecule binds to HIV, other regions of the CAR molecule signal the cell to become activated and kill the HIV infected cell.

The researchers found that, in test animals, modification of the blood-forming stem cells resulted in more than two years of stable production of CAR-expressing cells without any adverse effects. In addition, these cells were widely distributed throughout the lymphoid tissues and gastrointestinal tract, which are major anatomic sites for HIV replication and persistence in infected people. Most important, engineered CAR T-cells showed efficacy in attacking and killing HIV-infected cells.
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Luxturna for treating inherited retinal disease

Luxturna (voretigene neparvovec) is an adeno-associated viral (AAV) vector gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). Luxturna is approved for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients.

Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. Biallelic mutation carriers have a mutation (not necessarily the same mutation) in both copies of a particular gene (a paternal and a maternal mutation). The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision.

 Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patient’s vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision. Luxturna should be given only to patients who have viable retinal cells as determined by the treating physician(s).

 Treatment with Luxturna must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna. The most common adverse reactions from treatment with Luxturna included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear.
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