Tuesday, July 28, 2020

Italian gene therapy for metachromatic leukodystrophy

A family in Phoenix is desperately seeking help to afford a special treatment overseas after two of their daughters were diagnosed with an aggressive and debilitating brain disease that could ultimately kill them both one day.

Earlier this year, Dave and Kendra Riley's world was flipped upside down when they discovered that their 2-year-old daughter, Olivia, had a "highly progressive and rare genetic brain disease" called Metachromatic Leukodystrophy (MLD), according to a GoFundMe page set up on the family's behalf.

Months later, as Olivia's condition worsened to the point where she can no longer walk or talk, things became even more heartbreaking for the family after they welcomed their third daughter, Keira, and learned that she also has MLD.

As their days with Olivia become "limited," Dave, Kendra and their eldest daughter Eva, 5, now find themselves in a race against time to raise enough money by the end of July so that they can afford a special gene therapy treatment — only available in Milan, Italy — that could potentially save Keira's life.

"We have so much hope for Keira because of this treatment and want to do everything we can to give Eva (and ourselves) as many happy memories as we can with her sisters," the parents wrote on the GoFundMe. "Please help us raise enough funds to give our Keira the chance at a normal life; to save her life from the horrible disease that is MLD."

Dave and Kendra Riley. Two of their three daughters, Olivia (2 years old) and Keira (5 months old), have been diagnosed with Metachromatic Leukodystrophy (MLD)

Dave and Kendra first noticed something seemed wrong with Olivia in November 2019, according to the GoFundMe.

"Olivia began having difficulties walking, would tilt her head and we then noticed a vibration in the irises of her eye," Kendra explained. "Concerned, we took her to our pediatrician who suggested starting PT and going to an ophthalmologist."

The ophthalmologist ordered an MRI, and in the meantime, the Phoenix parents welcomed their third daughter, whom Kendra said was "perfectly healthy" at birth on Jan. 9.

But Olivia's condition continued to get worse, and Dave and Kendra were faced with even more of a challenge in getting her adequate medical attention due to the coronavirus pandemic.

After finally getting an MRI, which showed "vanishing white matter in her brain," and seeking out multiple opinions from neurologists, a genetic test confirmed that Olivia had MLD.

According to the U.S. National Library of Medicine, MLD is a genetic disorder that affects cells in the nervous system which produce myelin, the substance that insulates and protects nerves.

The disease causes a progressive loss of brain functions and motor skills, such as the ability to walk and speak. It also can lead to loss of sensation in the hands and feet, seizures, paralysis, blindness and hearing loss and eventually cause one to become unresponsive due to a "lost awareness of their surroundings."

In Olivia's case, because it presented so early, doctors have said she is not expected to live past 4 to 6-years-old, according to the GoFundMe.

"Dave and I were devastated. How could this happen to our sweet Livvy?" Kendra wrote, noting that she and Dave even had genetic testing done before they started having kids and were cleared from MLD. "Unfortunately, our form of MLD is so rare that they don’t even test for it, they only test for the five most common mutations."

Kendra and Dave eventually learned that they both carry the genetic mutation, which presents their kids with a 25 percent chance of developing MLD, so they immediately had testing done on Keira and Eva.

As they awaited the girls' results, the parents continued to take weekly trips with Olivia to Iowa, where she has been receiving treatment and medicine through a port.

"So far, we have not seen a difference but we are hopeful that it will slow the disease down so we have more time with her," Kendra wrote. "Olivia has lost her vocabulary, cannot pronounce most words, and experiences some form of pain (from moderate to severe) on a daily basis."
By June 19, results confirmed that Eva was a carrier for the disease like her parents, and will be unaffected by it, but her little sister had both mutated copies of the gene and MLD, according to the GoFundMe.

"Hearing that not one but two of my daughters’ lives will be cut short from this awful disease is too much to bare," Kendra wrote.

The parents said they immediately reached out to resources for MLD-affected families after the heartbreaking news and learned of "a cutting edge treatment option" called gene therapy, which could potentially give Keira the chance for "a normal life."

Unfortunately, the treatment is only available in Milan, and because the clinical trial was fully enrolled, Dave and Kendra said they would have to pay out of pocket for the family to move to Italy for five months.

Additionally, Dave and Kendra explained that if they were to temporarily move to Europe, they would also have to transfer Olivia's treatments there and make sure that their insurance will cover them.

"It will cost upwards of $500,000 for the treatment, lodging, travel and expenses for our girls’ day to day care," Kendra explained. "This does not include the trips we will need to take back to Italy every 6 months for Keira’s check-ups. Dave and I will also not be able to sustain a stable income while we spend this time with our girls."

With no other options, Dave's sister Nina Riley set up the GoFundMe on behalf of the family on June 25. Since then, they have raised over $171,000. A tax-deductible fundraising page was also set up on the Armer Foundation for Kids website.

"Your support will not only help save our daughter’s life but further the advancement of gene therapy, which has the potential to cure hundreds of rare diseases," Kendra wrote on the GoFundMe. "We could not thank you enough for any help or support during this time."

My advocacy for gene therapy dates back to July 5, 2012. That was the day a neurologist at Children’s Hospital of Philadelphia explained how my 2-year-old daughter, Cal, had late infantile-onset metachromatic leukodystrophy (MLD). It is caused by a single faulty gene that she inherited from both my husband and me. The genetics counselor explained that Cal had won the worst sort of lottery: MLD affects 1 in 100,000 children.

This genetic error causes fats known as sulfatides to accumulate in Cal’s cells. As they build up in cells that make myelin, the substance that insulates and protects nerves, they destroy tissue throughout the brain, spinal cord, and other parts of the nervous system.

At the time, there was no cure for MLD, and Cal was not expected to live beyond the age of 6.

A few days after the one-year anniversary of Cal’s diagnosis, Dr. Alessandra Biffi and her colleagues at the San Raffaele Scientific Institute in Milan, Italy, published a report in Science magazine about a revolutionary gene therapy for MLD. Biffi’s team had hoped the therapy would lead to a milder form of the disease. But some of the children who underwent the treatment were not developing MLD at all — a miracle to them and their families.

Cal once ran and read books and ate macaroni on her own. By the time we learned of the Italians’ breakthrough, she had stopped talking, could not see, and was essentially paralyzed. She gets nourishment through a feeding tube, and receives hospice care.

To help us cope with our grief, friends and neighbors started hosting bake sales to raise funds for fighting MLD. The first event raised $9,000. We weren’t sure what to do with it. Dr. Amy Waldman, Cal’s neurologist at Children’s Hospital of Philadelphia, made a suggestion that would change all of our lives. After reading the report by Biffi and her colleagues, she recommended that we help families get to Milan for the ongoing MLD gene therapy trial there.

Gene therapy works only to prevent the disease. Once symptoms appear, it can’t reverse the damage to the brain and central nervous system. “So how can we help other people’s children when Cal couldn’t be saved?” I asked Waldman. She explained that, since there is no newborn screening test for MLD, the birth of a child with the condition is a signal to test any other children the parents have later. So every child eligible for the gene therapy trial is a younger sibling of a child living with MLD.

A year later, when Cecelia Price from Omaha, Neb., was diagnosed with MLD because of her older sister’s diagnosis, the foundation we started was able to help send her to Milan to take part in the trial. Since then, we have sent 10 children to Italy: five from the U.S., two from the United Kingdom, one from Australia, one from Ireland, and one from Switzerland. Some of them now play baseball and soccer, attend school, and lead remarkably healthy lives. These children, who have outlived their siblings with MLD, became our investments in a miracle.


Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388(10043):476-487. doi:10.1016/S0140-6736(16)30374-9


Background: Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT).

Methods: This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure [GMFM] score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov, number NCT01560182.

Findings: Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18-54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients [grade 3 in four of five patients]). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% [range 14·0-95·6] lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites.

Interpretation: Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up.

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