US doctors customise drug to treat girl with rare genetic disease

Doctors in the United States have customised a drug to treat a girl with a rare form of genetic disease, opening avenues for the development of personalised treatments for people with life-threatening rare diseases. 

The child, Mila Makovec, now eight, was only three when the debilitating symptoms — onset of blindness, ataxia, seizures, and developmental regression — appeared, according to a study published in the journal New England Journal of Medicine.

By the time Makovec turned five, she began experiencing modest language and social regression, as well as increased clumsiness and stumbling.

As the symptoms accelerated, she lost her vision, had frequent falls, slurred speech (dysarthria), difficulty in swallowing foods and liquids (dysphagia). She was hospitalised, months before she turned 6, the study revealed.

By age seven, Makovec began experiencing 15-30 overt seizures per day and needed substantial support to walk. “She did, however, remain alert and reactive to familiar stimuli and responded happily to hearing her favorite books and songs,” the study noted.

After much evaluation, doctors at the Boston Children’s Hospital diagnosed Makovec with a form of Batten disease — a rare, fatal and inherited disorder that affects the retina and the central nervous system (CNS). The disease, caused by mutations in CLN7 protein, is recessive, meaning the patient inherits two mutated genes, one from each parent.

CLN7 (also known as MFSD8) is one of more than a dozen genes known to be associated with Batten disease, according to a statement on Boston Children’s Hospital’s website.

The mutation that Makovec inherited from her father was detected with standard clinical testing. But, the doctors had to examine her entire genome — and that of her parents and brother — to find the mutation that the girl shared with her mother.

The team led by Timothy Yu, from the Division of Genetics and Genomics at Boston Children’s Hospital, found that both Makovec’s and her mother’s CLN7 genes had a retrotransposon gene. The rare gene is often called as jumping genes because they can “hop” into DNA at various locations.

Within a year of the identification of the mutation, the team of doctors developed a tailor-made a drug, according to Makovec’s conditions. They dubbed it as “Milasen’ after the girl's first name Mila.

The Milasen drug substance (18 g) was manufactured and formulated for clinical administration, after receiving due permission from the US Food and Drug Administration. Initial tests in rats showed the drug to be effective, with no major side-effects. It was then administered to Mila in phases.

Within a month, of the first dose on January 31, 2018, the frequency of seizures showed a decline. As the treatment continued, it came down to between 0 and 20 seizures per day, and even the duration of each seizure decreased to less than one minute, the study revealed.

The mean age of patients at onset of CLN7 Batten disease was 3.3 years, and seven patients had died at a mean age of 11.5 years, according to the largest published case series of the disease, the team said in the study.

To fund the research and development of the drug, Makovec’s mother set up Mila’s Miracle Foundation and raised $3 million, the New York Times reported.

“Milasen itself remains an investigational drug, and it is not suited to the treatment of other patients with Batten disease because its design is customised to our patient’s specific mutation,” the researchers noted.

However, the study demonstrates the ability to “rationally design, test, and deploy a novel therapeutic agent for a patient with a rare disease”, they added.

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