The Daily News recently published an announcement by researchers at Sangamo Therapeutics showing the results of its first human trial to treat two rare genetic disorders through gene-editing technology.
Gene-editing (or genome-editing) is defined as “using biotechnological techniques to make changes to specific DNA sequences in the genome of a living organism.”
It is seen as the best hope for people with inherited disorders who, until now, have relied on having their symptoms treated but never cured or reversed. The theory is that altering the genes that carry the disorder would allow scientists to edit the mutations, thus curing the disease.
About the Trial
The first Sangamo trial involved two patients with rare genetic disorders that limit their ability to process certain sugars. This causes build-up in the brain, bone and other areas.
The gene therapy was delivered to the patients using proteins that bind to targeted segments of DNA.
One of the first participants was 44-year-old Brian Madeux, a Hunter syndrome (MPS II) patient. Brian’s genome was successfully edited but according to preliminary findings, researchers were not able to detect any of the intended effects of the therapy. It did not treat the disease.
Twenty-one months after the start of the trial, although the gene replacement was successful, the patients’ levels of the harmful, unprocessed sugars had not changed.
Mucopolysaccharidosis MPS I
- muco” refers to the thick jelly-like consistency of the molecules
- “poly” means many
- “saccharide” is a general term for a sugar molecule
Hurler syndrome (MPS I), is an inherited disease and the most severe form of MPS I. It is usually diagnosed in male infants who are deficient in an enzyme that breaks down glycosaminoglycans (GAGs). GAGs can be found in numerous cells anywhere in the body but particularly in fluid around the joints.
GAGs accumulate within the body and become toxic. The symptoms may be claw-like hands, heart or breathing problems, enlarged livers or spleens, loss of hearing, mental disorders and abnormalities of the joints and spine. The prevalence of Hurler syndrome is estimated to be 1 in 100,000.
Two milder subtypes of Hurler syndrome are Hurler-Scheie syndrome (intermediate severity), and Sheie syndrome (mild).
More information about Hurler syndrome may be found here.
Mucopolysaccharidosis MPS II
Hunter syndrome (MPS II) is similar in many respects to Hurler syndrome. Hurler syndrome and Hunter syndrome are members of the same group of inherited metabolic disorders.
However, their inheritance patterns differ in one distinct respect. Hunter syndrome is X-linked and Hurler syndrome is autosomal linked. Autosomal is simply any chromosome that is not a sex chromosome while the traits in x-linked inheritance are determined by the genes in a sex chromosome.
MPS I and MPS II are related to a more severe disorder known as Sanfilippo syndrome. It is called ‘childhood Alzheimer’s.’
Enzyme replacement therapy thus far has been shown to be the best treatment for these disorders. It can slow disease progression but it is not a cure.
More information regarding Hunter syndrome may be found here.
Latest Trial Results
Sangamo enrolled a total of nine patients who received replacement genes for its MPS I and MPS II trials. With respect to safety, the gene replacement had few side effects and the patients’ bodies started to produce the missing enzyme.
In addition, the urine tests showed falling levels of GAGs, which is a primary marker in their disease. However, the improvements did not last.
The most recent results show that the GAG levels of some patients did not show a significant change while others actually increased.
Brian Madeux and one other patient underwent successful changes in their genes and the replacement DNA ‘was permanently integrated into the genome. However, the therapy did not treat the disease itself.
Another Potentially Curative Therapy
Zinc finger nucleases (ZFNs), one of the earlier therapies, fuse two compounds that are engineered to seek out and cut segments of DNA.
These targeted genome therapies are engineered to correct inborn mutations for personalized cell replacement therapies.
About Genome Editing and CRISPR-Cas9
Through the use of gene-editing technology, genetic material may be removed, added or altered at various locations in the genome. One recently developed method is Nobel Prize-winning CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9.)
The CRISPR-Cas9 system is frequently headlined in news reports and has caused quite a bit of excitement in the medical community. It is cheaper, more accurate, faster and has proven to be more efficient than other genome-editing techniques.
CRISPR gives rare genetic disease patients encouragement, but it is not yet available for human trials.
Genome editing is the frontrunner in the treatment and prevention of human diseases. Most research on genome editing is currently being performed in order to understand diseases by using cells and animal models. Scientists are trying to determine its safety and efficacy on humans.
There are a wide variety of diseases being examined such as hemophilia, sickle cell disease, and cystic fibrosis. It is being considered for treatment and the prevention of even more complicated diseases such as heart disease, cancer, mental illness, and HIV infection.
CRISPR Arrays
The adaptation of CRISPR-Cas9 follows the pattern of a naturally occurring genome editing system found in bacteria. DNA segments known as CRISPR arrays are created when the bacteria capture fragments of DNA from invading viruses.
If the viruses attack again, the bacteria will “remember” the viruses and produce RNA segments from the CRISPR arrays which will target the viruses’ DNA. The DNA is then cut and the virus is disabled by the bacteria’s use of Cas9 or a similar enzyme. Researchers achieve similar results with the CRISPR-Cas9 in the lab.
Ethical Concerns
A considerable amount of controversy and ethical concerns surround genome editing when methods such as CRISPR-Cas9 are used to alter human genomes.
The changes that now occur with genome editing only pertain to somatic cells. These are cells that do not include egg or sperm cells. They affect certain tissues and are not passed sequentially through generations.
On the contrary, changes can be passed to future generations if they are made to genes in egg or sperm cells or in an embryo’s genes. Due to ethics and safety concerns, sperm cells (germline cells) and embryo genome editing are banned in certain countries. The ethical concerns involve the use of this technology to enhance such human traits as height or intelligence.
Although these results cast doubt about ‘fixing’ the genome, scientists hold out hope that raising the dose may bring improved results. There are over 6000 debilitating and deadly diseases in the genetic code. As one of the researchers said “. . . the theory – and the hope – is that if we can alter the genes that carry these diseases, we could edit mutations out of existence.”
