After their apparent success treating a young girl with a drug tailored to counteract a genetic mutation that had given her a usually fatal brain disease, the researchers behind the innovative strategy have this week laid out criteria for similarly helping more sick children. But the U.S. Food and Drug Administration (FDA) is cautioning that such one-off therapies need to be thoroughly considered before moving ahead and carefully evaluated, in part because desperate parents sometimes perceive improvements from a treatment that are not real.

In early 2017, after hearing of 6-year-old Mila Makovec, who had a condition called Batten disease that progressively damages brain cells and leads to death by adolescence, neurologist Timothy Yu of Boston Children’s Hospital and co-workers offered to try to help. They quickly designed and had a company synthesize a strand of RNA intended to mask a mutation in a gene called CLN7, which over time was causing Mila’s brain cells to accumulate waste and die. They first showed the potential drug, an antisense oligonucleotide that they dubbed “milasen,” could correct the CLN7 defect in cells cultured from her skin. With FDA approval, in January 2018 they then began to infuse the RNA into her spinal fluid. The team soon saw improvements in Mila’s condition, such as fewer and shorter seizures, Yu reported at a meeting 1 year ago.

Today, in a paper describing the case in The New England Journal of Medicine, Yu’s team reports that although Mila has continued to lose brain volume since treatment began, her seizures are still suppressed and her scores on neurological tests have mostly stabilized or improved. Her case is widely seen as a possible model for treating other individuals with certain disease mutations with a custommade oligonucleotide drug. Yu estimates that could include 10% of all cases of inherited central nervous system diseases.

However, because of the treatment’s risks, which include potential side effects from the drug and the procedure that delivers it into the spinal fluid, he and his colleagues write that the approach should only be considered for life-threatening brain or neurological diseases with no available treatment. Yu says his team isn’t ready to discuss any other families that have contacted the Boston lab. But one patient advocacy group has publicly shared that Yu’s team has designed an oligonucleotide for a toddler with ataxia-telangiectasia, a neurodegenerative disorder, and hoped to begin to treat her this fall. Yu has also offered advice to doctors treating a very sick young woman with an oligonucleotide matched to a mutation that has given her a form of amyotrophic lateral sclerosis.

In an editorial accompanying the paper from Yu’s group, FDA officials note that these single-patient studies—known as “n of one” because there’s just one patient—raise scientific and ethical issues. For example, regulators need to decide how much lab data are needed to show the treatment could work, and how to measure whether it is actually helping the patient. FDA, which met with Yu and Mila’s mother to discuss these issues in May, expects to continue to talk to researchers, patient groups, companies, and others in the coming months. An FDA spokesperson says the agency hopes to issue draft guidelines for testing customized therapies such as oligonucleotides within the next year.

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