A custom-crafted antisense oligonucleotide therapy (ASO) has
brought hope, and perhaps effective treatment, to a young girl with a rare form
of Batten disease—so rare, in fact, that she is likely the only person in the
world whose disease is caused by this particular mutation. Her treatment is
also unique to her. And as the ultimate example of “personalized medicine,” it
illustrates the potential of the genomic revolution in medicine, even as it
raises questions about how such uniquely crafted therapies can be offered to
other patients with other diseases.
“This drug is only applicable to our patient, not to others
with Batten disease,” said lead researcher Timothy W. Yu, MD, PhD, assistant
professor in pediatrics at Harvard Medical School and attending physician in
the division of genetics and genomics at Boston Children's Hospital. “But we do
think it has potentially broad implications.”...
The patient, a young girl, developed normally until 2016,
when, at the age of 4, she began to exhibit vision loss and gait impairment. By
age 6, her gait had worsened, her speech became slurred, her behavior
regressed, and her vision declined significantly. She was admitted to the
hospital, where tests showed retinal degeneration, cerebellar atrophy, and
subclinical seizures. Clinical genetic testing led to a diagnosis of Batten
disease, or neuronal ceroid lipofuscinosis, specifically CLN7-NCL, so rare that
only about 70 patients have been described in the literature.
“This is a terrible, terrible, diagnosis,” Dr. Yu said, with
invariable and rapid progression, leading to death at about 11 years of age.
“But in this case, there was a wrinkle, because she only had half a diagnosis.”
The genetic testing had turned up only one mutation in the
CLN7 gene, but all other known cases were autosomal recessive, with two
mutations. “So where was the second mutation?”
The family's geneticist told them they would need whole
genome sequencing to understand the full genetic picture. In late 2016, there
were relatively few labs in the country that could perform such sequencing with
very rapid turnaround, but a friend of the girl's family used social media to
plead for help. “That's where my lab came in,” Dr. Yu said, who became aware of
the case when his wife shared the social media post with him.
Members of his lab began sequencing, and by early 2017, they
had their answer: “Instead of finding a point mutation in the CLN7 gene, we
found a retrotransposon,” Dr. Yu said. Commonly known as “jumping genes,”
retrotransposons, which litter the genome, are mostly inactive, but
occasionally become transcribed into RNA, converted back into DNA, and then
randomly inserted back into the genome. “And if you are unlucky enough, it can
land in a critical neurogenetic disease gene, where it can disrupt that gene
and cause a disease. We discovered this is exactly what had happened in our
patient,” Dr. Yu said.
The retrotransposon had been inserted into the CLN7 gene
deep within an intron between exons 6 and 7—clinical testing did not detect the
mutation because the tests only look for exonic or near-exonic variants. The
insertion had created a new splice site, which in turn created a new exon, but
one that carried a stop codon, preventing protein production.
“So then we asked the question, could we fix this using an
antisense oligonucleotide to block the abnormal splicing?” Dr. Yu said. He was
“only emboldened to even think about this approach” because in December 2016,
the ASO nusinersen (Spinraza), which alters splicing, was approved for spinal
muscular atrophy, an autosomal recessive neurodegenerative disease.
“We decided to try to design an ‘N-of-one’ customized
therapy,” he said. [An “N-of-one is a study in which a single patient is the
entire clinical trial.] To do so, they combined a gene-specific screen in
patient fibroblasts, bioinformatics to predict the exact splice site regulatory
elements, design and synthesis of candidate ASOs, and cellular assays to
determine if the ASO improved cellular function. After discussions with the
family, they approached the US Food and Drug Administration (FDA) in August of
2017 to discuss their plans to move ahead if the preclinical results were
promising.
By October 2017, they had shown that one candidate ASO
partially corrected expression of the normal transcript, and cell assays
indicated it reduced storage material, shrank lysosomal mass, and corrected
lysosomal enzyme trafficking. “By every measure we looked at, our
oligonucleotide was improving lysosomal function,” Dr. Yu said. He named the
ASO “milasen,” in honor of his patient, Mila (her parents gave permission for
her name and details of the story to become public).
At the same time, though, Mila was declining, with many
prolonged seizures every day—“Time is running out,” her family said during that
summer. Dr. Yu's team began to create a plan to accelerate the rest of the drug
development process, including manufacturing, formulation, and animal toxicity
tests, and to design the elements of their N-of-one trial.
Through cooperation and tight coordination among the lab,
contract research and manufacturing organizations, and the FDA, all of that was
completed within four months. On January 31, 2018, Mila received her first dose
of the ASO, delivered intrathecally. Administration at escalating doses
continued every two weeks for 14 weeks, followed by maintenance dosing about
every three months.
“We are now a little over one year into our trial,” Dr. Yu
said. “The treatment is well tolerated, and there are no adverse effects
attributable to the drug.” As for outcomes, he stressed, “this is a single
patient,” with no control group, “but the family has reported substantial
stabilization compared with the steep decline she was exhibiting before
treatment.”
Supporting that observation are results from seizure
diaries. “At the beginning, there were up to 30 seizures per day, with almost
all of them lasting more than one minute. What we saw over the course of the
dose escalation is the frequency went down, and the intensity lessened, so that
almost none of them were over one minute.” That improvement has been
maintained, Dr. Yu said, over the first year. “We think of this as a very
promising early sign.”...
But in order to proceed with treatment, Dr. Bennett [Frank Bennett, PhD, senior vice president of research and
franchise leader for neurological programs at Ionis Pharmaceuticals, which
discovered and developed nusinersen] stressed, “you need to demonstrate that the ASO leads to a recovery of function,”
or a slowing of decline, which, as in Dr. Yu's case, required significant lab
resources in addition to the genomic and bioinformatic investments. It is
likely impossible to calculate the full cost of the development of milasen,
since much of the work was donated and done by volunteers, but a similar effort
done at market rates might approach one million dollars, he said.
“I don't see a way we can do this commercially with a viable
business model, but I do see ways, either through charities, or foundations, or
the NIH, that we can broaden the applicability of this to treat more patients,”
Dr. Bennett said. “Tim has opened a brave new frontier for us.”
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