First US attempt to cure a rare disease with genome editing fails miserably
- Scientists at Sangamo attempted the first human trial of a gene-editing method to cure rare, debilitating enzyme deficiency diseases
- After showing early promise, the DNA replacement failed to reduce levels of harmful unprocessed sugars
- The gene replacement itself worked, but after nearly two years of the trial, it does not appear to be a likely cure
- Sangamo holds out some hope that higher doses could work
- A newer gene-editing technology, CRISPR, has inspired even more hope for rare genetic diseases sufferers, but it is not ready for human trials
The first human trial of gene editing technology to treat a rare disease in the US has returned disappointing results, researchers at Sangamo Therapeutics announced today.
Gene-editing has been hailed as the best hope to treat inherited disorders.
Sangamo’s trial used proteins that bind to targeted segments of DNA to deliver gene therapy to three patients with a rare genetic disorder that disrupts their ability to process certain sugars, causing damaging build-up in the brain, bones and more.
But a year and nine months after the trial’s start, the patients’ levels of harmful sugars have stayed effectively the same, casting a disappointing shadow of doubt over the prospects for ‘fixing’ the genome.
Brian Madeux (center, file image) was among the first people to have his genome edited as part of the first US human trial to attempt to cure two genetic diseases. His genes were successfully edited, but the treatment has so far done little to change markers of the disease, according to preliminary findings of Sangamo Therapeutics trials released today
More than 6,000 deadly or debilitating diseases lurk in the genetic code.
Until very recently, all that could be done for people with these diseases was to treat their symptoms – there was no way to cure or reverse these conditions.
But the theory – and the hope – is that if we can alter the genes that carry these diseases, we could edit mutations out of existence.
One of the earliest, most promising methods for doing so uses so-called zinc finger nucleases (also referred to as simply zinc fingers, or ZFNs).
Zinc fingers are a fuse of two compounds that can be engineered to seek out and cut specific segments of DNA.
The latest advancements for gene-editing use the Nobel Prize-winning CRISPR technology, but the method is too new for human trials.
Scientists at Sangamo used these to target genes that code for two related disorders, mucopolysaccharidosis types I and II (MPS I and MPS II).
MPS I causes Hurler syndrome, a deficiency of an enzyme that, in healthy people, breaks down complex sugar chains called glycosaminoglycans (GAGs).
In those with Hurler syndrome, GAGs instead build up in the body, becoming toxic and causing symptoms like claw hands, deafness, heart problems, joint and spine abnormalities and worsening mental decline.
These children typically have coarse features, enlarged livers and spleens and may have heart and breathing abnormalities.
MPS II defects cause similar though slightly milder symptoms. Both conditions are more common among boys and affect one in 100,000 to 150,000 births.
Children with Hurler syndrome, such as this girl pictured in Sangamo’s presentation of their findings, tend to have coarse features and as harmful sugar chains build up in their bodies, the compounds become toxic, damaging organs and the brain
The two diseases are cousins of the rarer, more devastating Sanfilippo syndrome, known as ‘childhood Alzheimer’s.’
The best treatment for this family of diseases is enzyme replacement therapy, which can slow declines but is by no means a cure.
Between its trials for MPS I and II, Sangamo enrolled nine patients who received replacement genes.
In the technical sense, the experiment worked. The scientists saw that the gene replacement worked and caused minimal side effects. The patients’ bodies did begin producing more of the missing enzyme.
At least two study participants, including Brian Madeux, had their genes successfully changed.
But it didn’t work to treat the disease itself.
In earlier reported preliminary results, the study participants’ enzyme levels were seeing encouraging increases, and tests of their urine revealed falling levels of GAGs – the most important measure of their diseases.
These improvements didn’t last, however.
In today’s results, the patients’ GAG levels ‘did not show a meaningful change,’ and some even increased, said Sangamo CEO, Dr Sandy Macrae on a conference call.
The replacement DNA ‘was permanently integrated into the genome,’ a significant step forward, ‘but our mission is more leading the way scientifically,’ he added.
‘We are realistic about whether this first generation [treatment] is going to accomplish everything that these patients need it to.’
One patient struggled during the trial, and it was recommended that they return to the standard enzyme treatment (which most continued to receive though a few withdrew from it and a couple of others are considering doing the same).
The Sangamo scientists believe that, at higher doses, the therapy may still work, but today’s results are inevitably a blow to the hopes of sufferers of rare diseases for whom gene-editing has been an almost singular beacon.