Imma Perfetto
Cosmos science journalist
In a major step forward for gene editing, an infant’s rare genetic disorder has been successfully treated with a tailor-made gene therapy. The US team developed, tested, and obtained FDA approval to administer the personalised therapeutic in just 7 months.
The first of its kind achievement paves the way for similar therapies for other patients with rare diseases for whom no medical treatments are available.
The patient, named KJ, was diagnosed at birth with a rare enzyme (CPS1) deficiency which is normally needed to convert ammonia to urea in the liver. The deficiency causes ammonia to build up to toxic levels, which can result in organ damage particularly in the brain and liver.
The metabolic disease has a 50% mortality rate in early infancy.
The first dose of the experimental gene therapy to correct this mutation was delivered, with no serious side effects, in late February. This was followed by subsequent doses in March and April.
Since then, KJ has tolerated increased dietary protein, required less medication, and recovered from typical childhood illnesses without ammonia build up in his body.
“While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising,” says Dr Rebecca Ahrens-Nicklas of the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania in the US.
Ahrens-Nicklas is senior author of the case study published in the New England Journal of Medicine.
Associate Professor Samantha Ginn, a senior researcher in the Gene Therapy Research Unit at Children’s Medical Research Institute (CMRI) in Australia, who was not involved in the study, told Cosmos this is an “exciting step forward,” particularly for patients with rare and ultra rare diseases.
“Historically, gene therapies are designed to be applicable for all, or at least for the majority of patients with a particular condition.
“What sets this apart from other gene therapies, therefore, is that this treatment has been developed specifically for this patient with CPS1 deficiency. It cannot be used to treat another CPS1 patients carrying a different genetic mutation.
“The use of this technology represents a new era in gene therapy treatments, and we are just beginning to see its potential.”
Ginn adds that the short time from diagnosis to treatment is impressive.
“This group has been working quite closely with the FDA for a while now, trying to put together this pipeline and figuring out what the steps are … to translate a therapy very efficiently and quickly,” Caleb Lushington, a PhD candidate at the University of Adelaide (UofA) and the South Australian Health and Medical Research Institute (SAHMRI), told Cosmos.
“When they come across these very young patients with what they call n-of-1, or very rare disease genotypes, very quickly they can take the genetic landscape of that patient and put it into a disease model,” says Lushington, who was not involved in the research.
The team then rapidly screened different therapies in cultured human cells and animal models to identify the most efficient and precise gene editing approach in a short period of time.
“[It] is quite an achievement to be able to get this early, small release approval from the FDA,” says Lushington.
The therapy employed a type of genetic modification known as base editing, which homes in on a specific target DNA sequence and replaces a single base pair without introducing double stranded breaks in the DNA.
“In the past, gene therapies strategies have been what we now call ‘gene addition’ approaches, where we use a vector to deliver an extra copy of the mutated gene to restore function,” says Ginn.
“This therapy uses genome editing technology and has corrected the error in the genetic code unique to this patient.”
The US team packaged up the base editor into lipid nanoparticles (LNPs) – fat-like spheres which can encase, protect, and deliver therapeutic payloads into cells. LNPs are a relatively recent pharmaceutical advancement, and are critical to delivering mRNA vaccines for COVID-19.
“Part of the property of the lipid nanoparticle itself [is] that these lipids accumulate in the liver due to its general function of the filtering the blood,” says Lushington.
The gene therapy could therefore be administered to the patient via intravenous injection to correct mutations in cells within the liver.
“Previously … the editing has been performed outside of the patient. For example, in sickle cell anaemia, they’ll correct the [red blood] cells outside of the body and then put the blood back into the patient,” says Lushington.
“There’s a lot of new factors in the gene editing field that have been put together to make this happen … As someone coming up through the ranks of gene editing academia, it’s very exciting to see sort of the next pillar of gene therapies coming together.”
Dr Fatwa Adikusuma, group leader of the Gene Editing Technology and Therapeutics Laboratory at UofA and SAHMRI, told Cosmos that while that the new approach is exciting, it also has limitations to be overcome before it can be used to help a wider range of patients.
For example, since LNPs tend to accumulate in the liver, according to Adikusuma it would be very hard to target diseases that affect other organs with this approach.
And, while base editing was the perfect intervention for KJ and others who suffer from point mutations, he says it limits the mutations it can fix.
“There are so many diverse mutations occurring in patients, including insertion-deletions that are probably un-targetable with their approach,” says Adikusuma.
“I believe, with further development, it is possible to use prime editing which will [broaden] the patients that can benefit technology.”
Adikusuma is hopeful that the approach can one day be used for more common genetic diseases, for which developing gene therapies currently takes 5-10 years.
