Tag Archives: gene therapy

Scientists experiment with gene therapy for completely color-blind patients

A tiny fraction of the population suffers from complete color blindness that renders them unable to distinguish otherwise vibrant colors. Now, doctors in Germany have run a trial with an experimental gene therapy that aims to correct the rare condition.

Normal color vision vs achromatopsia (right).

Achromatopsia, or complete color blindness, is a condition characterized by the total absence of color vision. This is due to defects in the cone cells — specialized light receptors in the retina that are responsible for both daylight and color vision.

Those who suffer from achromatopsia can only see in black, white, and shades of grey. What’s more, such patients can also suffer from other problems with vision, including increased sensitivity to light and glare (photophobia), involuntary back-and-forth eye movements (nystagmus), and significantly reduced sharpness of vision (low visual acuity).

Around one-third of all cases of achromatopsia are caused by a mutation in the GNGA3 gene. This was the target of a novel gene therapy developed by the Institute for Ophthalmic Research at the University Hospitals in Tübingen and the Departments of Pharmacy and Ophthalmology at Ludwig Maximilian University of Munich (LMU).

Patients with achromatopsia are completely color blind. Their vision is blurred and their eyes are highly sensitive to bright light. Image and simulation: Stylianos Michalakis.

The therapy involves inserting the CNGA3 gene directly into a patient’s retina using a harmless adenovirus.

Weeks after the functional version of the gene is introduced in the target site, its expression starts producing proteins that should restore the function of the defective cones.

The researchers tried the therapy with nine achromatopsia patients aged 24 to 59 years.

“The experimental subjects suffered no drug-related health problems as a result, nor did their retinas show any permanent changes,” says Professor Dominik Fischer, who headed the clinical study.

No evidence of a cure but the study’s primary objective was a success

There was no clear positive effect in terms of the therapy’s efficacy. Although vision improved somewhat, both in terms of focus and in relation to color vision, the therapy cannot be considered by any means a ‘cure’.

However, curing the condition was not the aim of this study. Instead, the researchers’ immediate goal was to establish safety.

“The study is an important first step. It represents a milestone on the road to a curative therapy of achromatopsia, and we expect even better treatment success in the future,” said Professor Bernd Wissinger from the Tübingen Research Center for Ophthalmology.

According to the researchers, the regions of the brain responsible for processing vision lose plasticity in adulthood. Seeing how the brain of people with achromatopsia has never learned to process color information, they might not be able to see colors despite having improved cone functions. In other words, the software isn’t compatible with the hardware.

Now that the treatment is deemed safe, the researchers plan on repeating the trial with patients who are still children, whose brain plasticity and retinal tissue hasn’t suffered as much damage as adult patients.

“Since the gene vectors used have proven to be safe, a follow-up study in pediatric CNGA3 patients is possible and useful,” says Stylianos Michalakis from the Department of Ophthalmology at LMU.

The findings appeared in the journal JAMA Ophthalmology.

CRISPR gene-editing therapy inserted in the human body for the first time

In a world’s first, scientists have directly administered a CRISPR–Cas9 gene therapy in a patient suffering from a hereditary blindness disorder. The clinical trial, named BRILLIANCE, is still ongoing.

Credit: NIH Image Gallery.

The aim of the trial is to see whether removing a mutation that causes Leber’s congenital amaurosis 10 (LCA10) — the leading cause of childhood blindness in the world for which there is no cure — might reverse the disease.

Researchers at the Oregon Health & Science University in Portland, in collaboration with pharmaceutical companies Editas Medicine (USA) and Allergen (Ireland), encoded the components of the CRISPR gene therapy into a virus that was injected directly into the eye of the patient.

The therapy targets a mutation in the gene CEP290 that is known to cause LCA10.

Previously, clinical trials involving CRISPR-Cas9 edited the genomes of cells that had been removed from the body and later infused them into the patient. In contrast, this time the therapy was inserted directly into the live human body.

For now, there are no details concerning the procedure, such as when it took place or how the patient is fairing. According to the researchers though, it might take a month before the patient should start restoring vision.

However, this isn’t the first time that gene-editing has been used in the human body. Previously, researchers used an older gene-editing technique called zinc-finger nuclease on live patients suffering from Hunter’s syndrome. The results suggest that the procedure was safe; however, there were little signs that the disease’s symptoms improved.

Scientists think that BRILLIANCE is different, betting on CRISPR-Cas9’s superior accuracy and versatility. What’s more, other gene-editing techniques aren’t suited at all for treating LCA10 since they typically require inserting a healthy copy of the mutated gene into the affected cells. The CEP290 gene, however, is much too large to fit into a viral genome. With CRISPR, you don’t have to insert the entire gene — you simply encode instructions that remove the mutation.

Patients suffering from LCA10 still have photoreceptors in their retina that should theoretically allow them to see — it’s just that the mutation disables these cells. Scientists hope that once the therapy advances, these sensing cells will become activated and the patient will be able to see.

“This is one of the few diseases where we think you could actually get an improvement in vision,” Mark Pennesi, a specialist in inherited retinal diseases at Oregon Health & Science University in Portland told Nature.

There shouldn’t be any safety issues since the gene-editing tool stays in the eye and doesn’t travel to other body parts.

Even if the therapy doesn’t work as intended, the trial is a milestone in gene editing, signaling that medicine is ready to make the leap from treating cells in a dish. And if all goes well, researchers plan on testing the therapy on 18 children and adults.

Gene therapy creates new skin for boy with rare, devastating condition

A boy suffering from a disease which causes untreatable wounds over 80% of his body has been given a second chance at life. Doctors in Europe repaired and then replaced his skin with a new, disease-free version.

The skin has its own stem cells which enable it to renew itself time and time again.

Hassan, who lives in Germany, suffers from junctional epidermolysis bullosa. This leaves his skin as fragile as butterfly wings, vulnerable to blistering and erosion. The prognosis was grim for Hassan — his chances of living were deemed slim at best. But a new therapy changed all that. Two years ago, doctors harvested samples from his skin, genetically modified them to repair the DNA and eliminate the disease, and then grafted this version back to the boy. Now, two years after the procedure, Hassan seems to be healthy. He is living a normal life, enjoying it as a kid should, his father says.

“Hassan feels like a normal person now, he plays, he’s being active, he’s enjoying his life and he’s not the way he was before,” he said.

A sheet of the laboratory-grown, genetically modified skin. Photograph: CMR Unimore.

Hassan was born in Syria. Ever since he was a few days old, he’s had blisters all over his body. His parents didn’t know what to do and treatment options were extremely limited. Finally, the family fled Syria and arrived in Germany. They checked in at Children’s Hospital at Ruhr-University, in Bochum, Germany, in June 2015. By then, Hassan was lacking 80% of his skin, his body turned into a big, red, blistering wound.

Doctors tried conventional treatments (like grafting skin from Hassan’s father), but that quickly failed. They resorted to palliative care and giving him morphine to ease the pain, and it seemed that was all they could do for the boy. Dr, Tobias Hirsch, from the hospital, said:

“We initially decided to provide palliative care because we had no chance to save the life of this child.”

But everything changed when a team of biologists specializing in gene therapy was brought in from the University of Modena and Reggio Emilia. As a last ditch resort, they wanted to try an experimental therapy. It’s not the first time something like this was attempted but it’s by far the most body surface was covered in a patient: 9 square feet (0.8 square meters) — almost his entire body.

The Italian team which led the procedure was led by Michele De Luca.

“This is the first time that such an amount of body has been transplanted,” said De Luca. “He basically lost almost completely his epidermis.”

The approach was successful thanks to the structure of the skin itself. Human skin contains its own specialized stem cells, which allow it to be renewed constantly throughout life. This also allows scientists to grow grafts in culture from small samples. Integration is also fairly easy. In Hassan’s case, it only took a month for Hassan’s body to renew and sustain the healthy skin.

However, he had to be put into an induced coma for more than four months to be spared from the excruciating pain.

“Once you have regenerated the epidermis, the stem cells keep making the renewal of the epidermis as in a normal [healthy person],” said De Luca. “All the data we have … are telling us that this is going to be a stable situation.”

This technique gives hope to thousands of people suffering from the same condition. About 25,000 people in the United States have it, and 500,000 worldwide, and there is no established cure for it. The degree of severity varies, but many of these people spend their entire life in severe pain. Some never live to reach adulthood. However, it’s not clear if the same approach can be used for all cases. Jouni Uitto, the chairman of the department of dermatology and cutaneous biology at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia also warns that epidermolysis bullosa sometimes affects internal structures, such as the lining of the esophagus and urinary tract, and gene therapy for skin cannot address these problems. But for people like Hassan, a treatment cand make all the difference in the world.

Journal Reference: Tobias Hirsch, Tobias Rothoeft, […]Michele De Luca. Regeneration of the entire human epidermis using transgenic stem cellsdoi:10.1038/nature24487

Reconstructive surgery (credit: U.S. Army/Nashaunda Tilghman/Wikimedia Commons)

Plastic surgery of the future will rely on gene therapy

Reconstructive surgery (credit: U.S. Army/Nashaunda Tilghman/Wikimedia Commons)

Reconstructive surgery (credit: U.S. Army/Nashaunda Tilghman/Wikimedia Commons)

Reconstructive surgery has made huge strides forward in the past few decades alone, helping countless people live a life closer to normal, freer from the immense harshness and pain that comes with damaged and exposed tissue. In the future, regenerative surgery will only evolve, and gene therapy is set to play a major role.

A recent study looked to assess the progress toward developing effective gene therapies for use in regenerative surgery. Researchers Padua University Hospital, Italy, led  by Dr. Giorgio Giatsidis, found that a number of promising  techniques have been reported  that use gene therapy to grow skin, bone, and other tissues for reconstructive surgery. Moving them from the lab to the surgery room will however prove to be the biggest challenge the scientists working in these fields need to face.

“After two decades, regenerative surgery is an adolescent looking forward to growing up,” Dr. Giatsidis and coauthors write. “Despite extensive preclinical approaches, translation of gene therapy strategies into clinical trials is still a difficult and expensive process.”

What’s so appealing about gene therapy is that it can be employed to promote growth of just about any kind of tissue. These tissues can then be used for more efficient regenerative surgical treatments for numerous clinical needs. For instance, the review mentions tissue-engineered products to promote healing of diabetic skin ulcers, techniques using transplantation of genetically modified donor bone to promote bone growth,  joint cartilage regeneration in patients with rheumatoid arthritis. Techniques to promote healing of tendons, regeneration of injured nerves, and growth of skin flaps for reconstructive surgery are all being explored.

With a way of readily growing tissue, surgeons would address their current biggest problem: lack of donor tissue. Small burns, for instance, can be easily corrected by transferring skin flaps from other parts of the body. If a person, however, has burns over a large surface of the body, then this technique won’t work so well for him. The same is for broken or shattered bones, muscles and the likes. Gene therapy sounds like a life saver, however the researchers first need to find a way to clinically introduce these techniques in an efficient and cheaply manner.

So far, the studies of diabetic ulcers and rheumatoid arthritis mentioned above are the only methods to show evidence of clinical effectiveness in human patients. “Even so,” the authors add, “cutting-edge gene therapy-based strategies in reconstructive procedures [are close] to setting valuable milestones for development of efficient treatments in a growing number of local diseases and injuries.”

The review was published  Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c) SPL / Photo Researchers, Inc

Deafness cured by gene therapy

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c)  SPL / Photo Researchers, Inc

Hair cells located in the organ of corti, in the cochlea of the inner ear.(c) SPL / Photo Researchers, Inc

A stroke of pioneering science, researchers have managed to restore hearing to a significant level in guinea pigs by using gene therapy, bolstering hope for a similar procedure to cure human deafness in the future.

The therapy works by promoting the regeneration of hair cells in the cochlea, the part of the inner ear which registers sound. These hair cells act like tiny dishes that catch infinitezimal fluid motion and transmit them into nerve signals to the brain, which we typically recognize as sound. These tiny hairs are incredibly sensitive, and it’s common for them to deteriorate or even get completely distroyed when exposed to loud sounds, certain drugs or old age, ultimately.

“It’s the first time anyone has biologically repaired the hearing of animals,” says Yehoash Raphael at the University of Michigan in Ann Arbor, Michigan, and head of the US-Japanese team that developed the technique.

For their research, the scientists first destroyed the inner-ear hair cells in guinea pigs. Then they injected a specially engineered adenovirus, the key to the treatment. This virus is completely harmless and contains a  gene called Atoh1 or Math1, which gets infused to the cells inside the scala media, the chamber where the tiny hearing hairs lye. The gene then generates a signalling molecule known to orchestrate the development of hair cells in embryos.

“The recovery of hair cells brought the treated ears to between 50% and 80% of their original hearing thresholds.”

By all means, these are incredible results. Moroever, the researchers report that hair cells were generated from other cells lined in the scala media, meaning some cells had been turned into other cells. Incredible!

The researchers hope this therapy might be used in the future on humans, at least as a complementary measure for people already using hearing aid devices. Raphael says that the next experiments in guinea pigs will focus on this combination. However, guinea pigs are far different from humans. For one, the inner-ear is nested deep inside the skull for humans, making surgery extremely difficult*, and there’s always a big chance the immune system will reject the researcher’s engineered virus. Let’s hope for the best.

The researchers’ findings were published in the journal Nature Medicine.

 *edit: in the initial draft of this article I wrote that inner-ear surgery in humans is impossible, which is a false statement. This type of procedure is difficult, but possible. Many thanks to Paul Harris for the input. 

Algae gene therapy could cure blindness

Researchers have managed to restore light perception to mice through gene therapy, by inserting algae genes into the retina. The treatment has succeeded in restoring the ability to sense light and dark to blind mice, and clinical trials in humans could begin in as little as two years.

“The idea is to develop a treatment for blindness,” says Alan Horsager, a neuroscientist at the Institute of Genetic Medicine at the University of Southern California, Los Angeles, who leads the research. “We introduce a gene that encodes a light-sensitive protein, and we target the expression of that gene to a subset of retinal cells.”

It is estimated that over 15 million people worldwide suffer from one form or another of blindness, like the most common retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Most affections relate to the photoreceptors in the retina, which transform light hitting the eye into electrical impulses, this way preventing the brain from receiving image information.

Scientists based their very creative gene therapy on the Channelrhodopsin-2 (ChR2), a photosensitive protein used by unicellular algae to help them move towards light, which they injected into the mice retina via a “domesticated” virus. The procedure was conducted on three groups of mice: one with normal vision, and two groups of mouse strains that naturally become blind with age in a similar way to people with RP and AMD. One of hte blind groups was subjected to gene therapy.

After dissection, treated mice reveled in their retinas that the  ChR2 protein was being indeed expressed by the bipolar cells. The biggest revealing data which poised researchers to believe their on the right track is their maze experiment in with blind and treated mice alike were put in the middle of a 6 corridor maze, with only one possible exit which was lighten. Scientist found that treated mice managed to find the exit on average 2.5 times faster than untreated blind mice.

“It’s a good paper, and it’s clear that they are heading towards a clinical trial with the information they are gathering,” says Pete Coffey of the department of ophthalmology at University College London. But he points out that although there is a statistical difference between the performance of the treated and untreated mice, that difference is small.

Even though this particular research, published in Molecular Therapy, might only render human patients to experience light/dark discrimination, it’s still some sort of progress, different from current non-commercial stem cell treatments, and in my opinion provides a definite step forward to curing what’s maybe one of the most tragic, yet common, affections of humanity.


Gene therapy for Parkinson disease boasts remarkable results

While gene-therapy is still regarded as a very innovative practice, it seems like the procedure might take traction as of today when remarkable results were concluded after the first successful double-blind gene therapy for Parkinson disease. In the case of this dreadful disease, medical researchers injected patients with a a gene that codes for glutamic acid decarboxylase (GAD), an enzyme that catalyses production of an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA).

Usually Parkinson patients produce too little GABA in their brains, and as a result overstimulation in an area of the brain called the subthalamic nucleus occurs, which in turn inhibits dopamine secretion, which is vital for movement. This is why Parkinson patients are described as having tremors, sluggish movements, rigid muscles and impaired posture and balance.

Andrew Feigin of the Feinstein Institute for Medical Research in Manhasset, New York, and colleagues conducted a double-blind test for GAD gene-therapy on a group of 65 patients. In this particular case, double-blind test refers to the fact that patients were grouped into patients who received a placebo surgery (a simple saline solution injected in the back of the skull) and those receiving real surgery (the skull was drilled and a virus containing the GAD gene was injected). Neither patients, nor researchers knew who was given a placebo or not when test results came in, apart from the surgeons – hence the double-blind test.

In the trial, 22 Parkinson’s patients had a gene inserted in their brains to produce more GABA, while twenty-three patients received the placebo. Six months later, researchers analyzed the results and came up with something remarkable – gene therapy patients showed improvements in their motor functions of 23.1 per cent, while also remarkably interesting those who were given a sham procedure scored an improved of  just 12.7 per cent.  The researchers rated the patients’ symptoms, including the severity of tremors and stiffness, and came up with a single “motor score” that represented how well they could move.

The treatment is intended for a subgroup of Parkinson’s patients — those who do not respond to medication very well. Of the 1 million to 1.5 million Americans with Parkinson’s, about 10 to 15 percent of them, or 100,000 to 200,000 people, fit into this category, said study researcher Dr. Michael Kaplitt, vice chairman for research in the Department of Neurological Surgery at Weill Cornell Medical College in New York.

The therapy came just in time for Dr. Walter Liskiewicz, 60, a Jackson oral surgeon so disabled with Parkinson’s that he could not walk before his July 2009 procedure.Now, he not only walks with a cane but he’s back playing a harmonica and writing smooth jazz.

The study “brings us much closer to having a gene therapy that might be ready for general use,” Kaplitt said. The work paves the way for gene therapies for other types of brain diseases, he said. “I think we are now helping to facilitate and to accelerate the development of a whole host of gene therapies … for diseases such as Alzheimer‘s disease, epilepsy [and] depression,” he said.

The results are indeed very satisfying, but since the actual procedure was made only on 22 Parkinson patients, further investigation is required.

image via knowabouthealth.com