By Prof Louis C H Fourie
JOHANNESBURG - Mila Makovec is a little girl that suffered from a debilitating illness, Batten disease, caused by a rare genetic mutation.
The genetic disorder is known to cause blindness, seizures and other neurodegenerative problems.
It is so extraordinarily rare that there was no known treatment available, and even worse, no scientists were researching the specific disease, thus leaving the family in a rather hopeless situation.
Fortunately, scientists have been experimenting with new classes of drugs that can be personalised very precisely according to a person’s genes, giving people with a rare disease, caused by a genetic disorder, a new lease on life.
Mila was treated in this way and became the first person in the world to receive this type of personalised treatment. In the New England Journal of Medicine, it is stated that scientists developed a tailormade treatment within one year of identifying the specific genetic error in her DNA. The drug was aptly called Milasen after Mila.
These new personalised medicines usually take the form of gene replacement, gene editing or antisense. In the case of Mila, the type used was antisense that functions almost like a sort of molecular eraser, which erases or corrects erroneous genetic coding.
Although the treatment has not totally cured Mila, it has stabilised her condition by reducing her regular seizures and enabling her to stand and walk with the help of other people.
Similarly, three-year old Ipek Kuzu had an exceptionally rare genetic mutation (ataxia telangectasia or A-T disease) that disrupted the ATM protein crucial for DNA repair, causing her to constantly lose brain cells. The disease already affected her walking and talking. Her parents were told that there was no cure for this disease and that she would probably not get older than 25 years.
After much research and effort, her father, Google programmer Mehmet Kuzu, eventually succeeded in convincing scientists and funders to treat his daughter’s rare genetic disorder with a novel personalised antisense drug engineered by doctors specifically for her. Ipek thus became only the second person in the world to receive a customised antisense oligonucleotide drug specifically designed to compensate for the DNA error by allowing her cells to splice together a functional version of the ATM protein.
What makes these personalised drug treatments so different from other drug treatments is that they can be programmed, in digital fashion and with digital speed, to correct or counteract inherited diseases. The development of gene medicine is thus much faster and more successful in the treatment of certain diseases. In the case of Ipek, the individualised genomic drug took Tim Yu, a paediatrician and geneticist from Boston USA, only a few months to create.
Hyper-personalised medicine is the beginning of a revolution in tailored genomic medicine, which started with the capability of high-speed gene sequencing. It is now possible to determine a baby or person’s full genome for a few thousand rand, as well as locate DNA coding errors that often cause rare conditions in people. This how the doctors diagnosed the rare diseases of both Mila and Ipek.
These specialised and personalised antisense treatment of Mila and Ipek started with the development of a drug called Spinraza for the treatment of spinal muscular atrophy. Although is not as rare as Batten disease or ataxia telangectasia, spinal muscular atrophy effects 1 in 10 000 babies and is a fatal disease. Spinraza was literally the key to the tailormade antisense drugs used in the cases of Mila and Ipek.
Spinraza was one of the first successful medicines made using an antisense oligonucleotide – a customised strand of RNA. Antisense acts at the level of RNA and keeps the mutated and faulty DNA messages from being translated, or modifies the translation. The cells of healthy people contain a protein SMN that helps motor neurons survive and grow. A gene called SMN1 contains the instructions to make this protein. However, people with spinal muscular atrophy have a mutation that disables the particular gene.
Fortunately, human DNA contains a second copy of the gene, named SMN2. This gene is inactive due to a small error that keeps the RNA message from being spliced together in a proper template. The Spinraza molecule contains a short segment of antisense RNA that prevents the slicing error and thus allows the body to start making the motor neuron protein.
Dr Timothy Yu has built on this ground-breaking work when he sequenced the genome of Mila Makovec and realised that Mila’s disease was caused by a splicing error very similar to the one that causes muscular atrophy, except that in Mila’s disease it disrupted a different protein, namely CLN7. Dr Yu used the backbone of the Spinraza molecule and attached a personalised strand of antisense RNA to enable Mila’s cells to start making functional copies of the CLN7 protein.
In similar fashion Dr Yu developed the drug atipeksen for Ipek to correct the way in which Ipek’s cells interpret her genetic information so that she will make a functioning copy of the ATM protein. This is where hyper-personalised medicine started because the treatment drug was tailored to the needs of a single patient.
Eventually, there is hope for people with the unbearable burden of genetic disorders, but unfortunately these drugs can only be used for the person for whom it has been designed. This goes against the current pharmaceutical practice where drugs are sold as widely as possible to recover the design, long development, manufacturing and testing costs. Although novel personalised medicine can make a huge difference in the lives of people with rare genetic mutations, it is currently hugely expensive and out of reach of most people.
In the case of Ipek Kuzu the manufacturing and testing costs were R33.4 million. This raises the question of how soon hyper-personalised treatments for rare genetic disorders will become more widely accessible and affordable. Some of the pharmaceutical companies are investigating the possibility of scaling these treatments, by possibly creating a pipeline for hyper-personalised drugs.
Co-founder of Ionis Pharmaceuticals, the manufacturer of Spinraza, started the n-Lorem Foundation to develop hyper-personalised treatments for patients. If they could succeed in developing drug templates and more easily change the part of the drug that is doing the targeting of different genetic diseases, the cost of these personalised drugs may come down significantly.
Since this earlier work several projects have been initiated, such as customised diabetes treatment that automatically adjusts the insulin levels and 3D printed personalised vitamins.
It is not clear yet, which diseases will be helped most by hyper-personalised medicine. In the cases of Mila and Ipek the hyper-personalised drug has certainly helped, but if it has cured the disease is too early to say. But without doubt, genetic and hyper-personalised drugs are the future for diseases caused by rare genetic disorders. Hyper-personalised medicine brings hope to numerous people who suffer from incurable diseases.
The important Fourth Industrial Revolution fields of biotechnology and genomic medicine are indeed promising. Multiple innovations such as gene editing, gene replacement, and other emerging technologies can be programmed digitally to correct DNA letter by letter. It is not only the confluence of technology that makes these treatments possible, but the digital nature of new medical technologies.
Hyper-personalised medicine could be a divergent technology that changes medicine forever. Just imagine a personalised pill created using your own unique DNA, which would give you vitamins, nutrients, or whatever your body lacks based on your DNA.
Prof Louis C H Fourie is a Futurist and Technology Strategist.
BUSINESS REPORT