Wednesday, December 16, 2015

Globoid cell leukodystrophy

Ungari S, Montepeloso A, Morena F, Cocchiarella F, Recchia A, Martino S,
Gentner B, Naldini L, Biffi A. Design of a regulated lentiviral vector for
hematopoietic stem cell gene therapy of globoid cell leukodystrophy. Mol Ther
Methods Clin Dev. 2015 Oct 14;2:15038.


Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation.

Lattanzi A, Salvagno C, Maderna C, Benedicenti F, Morena F, Kulik W, Naldini
L, Montini E, Martino S, Gritti A. Therapeutic benefit of lentiviral-mediated
neonatal intracerebral gene therapy in a mouse model of globoid cell
leukodystrophy. Hum Mol Genet. 2014 Jun 15;23(12):3250-68.


Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30-50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.

See: Treatment of globoid cell leukodystrophy May 15, 2015


  1. Naldini L. Gene therapy returns to centre stage. Nature. 2015 Oct 15;526(7573):351-60.


    Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.

  2. Facebook followers of “Addilyn’s Journey of Hope” read a post on the page Wednesday they’ve been praying wouldn’t come this soon: “Addilyn Sophia Davis earned her angel wings at 8:23 this morning.”

    Addilyn was 4 years old when she died Wednesday morning, two years longer than most infants with the fatal degenerative disorder Krabbe disease are expected to live.

    Since 2013, Addilyn’s mother, Jamie Davis, of New Sharon, has documented the journey of her daughter and her family on Facebook as they’ve grappled with her illness. In the two years the group has been active, it has grown to include 116,513 followers.

    Davis also fought for awareness of the disorder and those like it, including pushing for legislation this year to add Krabbe disease and similar disorders to the list that are screened for at birth under Maine law. The bill didn’t pass because there hasn’t been enough research yet on the disorder, said Rep. Andy Buckland, of Farmington, one of its sponsors...

    The posts fluctuated depending on the day. Some days they were frantic, the voice of a mother watching her child suffer. “She’s not well. High heart rate, high fever, high respiratory rate … Please, I beg you to pray for her comfort,” Davis wrote on Oct. 16.

    But there were also posts such as the one Davis wrote Monday, posts that depicted a mother in awe of her child.

    “Her strength, resilience and beauty radiates and never ceases to amaze me. She is a gift, a blessing and a miracle. This journey is hard; her fight remains harder. She’s peaceful, she’s content, she’s happy and she’s loved,” Davis wrote late Monday night, 36 hours before her daughter would succumb to the struggle she had been fighting since birth...

    Former Rep. Lance Harvell, who represented Farmington and Industry, said in his testimony that one of the struggles that parents of children with the disease go through is that while waiting for doctors to diagnose the rare disease, the symptoms look like those of a baby born of a drug-addicted mother.

    “My sense was that what most upset her is that a doctor is assuming what he is looking at is a cocaine baby,” Harvell told the committee. “Jamie’s a young woman, and this is in all likelihood what a doctor has far more seen. She’s trying to tell that doctor that ‘I’m not a drug addict,’ and that doctor is thinking, ‘People lie about drugs. That’s what I’m looking at.'”

    Harvell told the committee Jamie Davis’ passion for the cause drew him in.

    “She said normally mothers, when they have daughters, they are planning for their weddings and their children. And she said, ‘I’ve been planning for a funeral her whole life,'” Harvell said...

    Because of the complexity and the rarity of the disease, screening for its presence in newborns is not yet up to the precision that the Maine Center for Disease Control requires to screen for disease. Buckland said since screening is still at research level, the Health and Human Services Committee was reluctant to add it to the scientifically sound mandatory screening list.

    After the bill failed, Buckland wrote a letter in which he acknowledged the Davis family for their strength in caring for their daughter and their effort in bringing awareness to Krabbe disease.

  3. It’s not every day the Clemson spirit squad band and mascot parade to the home of a 10-month -old baby. But then again, Addison Grace is one unique little girl.

    “It just filled my heart,” said Stephanie Bolt, Addie’s mom.

    “Clemson is coming to them, so this is going to be cool,” said Jill Lancaster, ahead of the big surprise.

    Addie was diagnosed with Krabbe disease at 3 months. It’s a rare fatal genetic disorder that destroys the protective coating of nerve cells in the brain and throughout the nervous system. Babies with the genetic disorder usually don’t make it past age two.

    “She was all smiles and unfortunately the disease just takes that,” said Tammy Maddox, Addie’s grandmother.

    “She is comfortable. She is loved obviously and so that is all we need,” Jonathan Bolt, Addie Grace’s dad added about their last few months.

    Her parents don’t know how long she has, so early on they made a bucket list for their baby girl. On the top of that list was to take her to a Clemson football game. But that dream was squashed, when Addie Grace’s condition got worse.

    “We’re going to take my daughter and she is going to wear a little cheer leading outfit. It’s going to be so adorable, right?,” Jonathan asked. “And then it was like, well all of that is not going to happen now.”

    That is until Sunday afternoon when the Clemson band cheerleaders and Piedmont community brought the game to her. Hundreds gathered to cheer on the family. Addie even got a signed football with well wishes from Clemson Coach Dabo Swinney...

    The big surprise was actually set up by a man in Pennsylvania John Neal and the Clemson band director. Neal lost a child to Krabbe disease and has become an advocate for other families. He met the bolt family on Facebook and says he wanted to help fulfill their bucket list.

  4. (see above) UPDATE: Baby Addie Grace, who was diagnosed with Krabbe disease, passed away Thursday morning.

    Addie was diagnosed at 3 months. It’s a rare fatal genetic disorder that destroys the protective coating of nerve cells in the brain and throughout the nervous system. Babies with the genetic disorder usually don’t make it past age two.

    “She was all smiles and unfortunately the disease just takes that,” said Tammy Maddox, Addie’s grandmother.

    “She is comfortable. She is loved obviously and so that is all we need,” Jonathan Bolt, Addie Grace’s dad added about their last few months.

  5. Parents Tony Rushe and Jenna Bannon were devastated when their baby son Anthony was diagnosed with a rare and incurable disorder when he was only a few months old.

    Anthony, who had Krabbe Disorder which affects only one in 100,000 babies, died a year ago just after his first birthday. His heartbroken parents now have new joy in their life with baby Ashleigh who made her arrival into the world against all odds...

    To begin with Anthony progressed well and to their delight, he started smiling at his parents.

    However, from the age of about two-and-a-half months, he began crying a lot through the day and night.

    When he cried, Anthony gasped a lot causing wind to become trapped and build up. As a result, doctors and health visitors believed his crying was caused by colic which is very common in babies.

    Tony and Jenna tried everything from changing Anthony’s formula to a variety of colic medication but he carried on crying. As he was their first baby, they thought it must just be the norm.

    However, Jenna’s mother’s instinct prompted her to go to a GP again and she told him she thought something was very wrong and that she wanted Anthony checked over.

    The doctor agreed and noticed Anthony was floppy and not holding his head up. He asked Jenna when Anthony had last smiled and she told him not since he was two-and-a-half months...(continued)

  6. (continued)When she was 11-weeks pregnant, Jenna had to go to hospital to have a Chorionic villus sampling test (CVS).

    This test is offered during pregnancy if the baby has a high risk of a genetic disorder. With Anthony having had Krabbe Disease, they wanted to make sure the new baby didn’t have the condition too.

    The CVS test involves removing and testing a small sample of cells from the placenta.

    Jenna explains: “The test involved them putting an injection into my belly to take the cells from my placenta.

    “When they did it, they accidentally ruptured the amniotic sac which the baby was in and my waters started leaking out.

    “I only realised a bit later as every time I moved, my waters would gush out.”

    The concerned couple rang the doctor and went to primary care and a specialist midwife then arranged for them to have a scan.

    To their despair, Jenna and Tony were told that Jenna had lost all her waters and to go home and expect a miscarriage.

    Jenna says: “The sonographer told us she couldn’t see any water and as she didn’t want to give us any false hope, she told us it was unlikely our baby would survive.

    “When we asked what the chances were of the baby surviving, she told us one in a million"...

    “It didn’t seem right. How could Anthony die and then we see Ashleigh’s heartbeat two days later only for her to not make it?

    “I knew in my heart that Ashleigh would survive.”

    Jenna went home and lay on motionless for three weeks. As the test was done on her right hand side, she lay on her left.

    Jenna says: “I lay down for three weeks and didn’t move apart from to go to the bathroom.

    “I wanted to do everything I could for the baby.

    “We then went back to the hospital for a scan and they discovered the waters had built back up again despite it being a one in a million chance.”

    Jenna firmly believes Anthony is watching over his little sister and looking out for her. From the moment she and Tony first saw Ashleigh’s heartbeat, they have felt Anthony’s presence.

    Jenna says: “When we first saw Ashleigh’s heartbeat, I felt Anthony was there and when the hospital told us that my waters had miraculously built back up, I felt Anthony had played a part in it.

    “The test revealed Ashleigh does not have Krabbe’s Disease.
    “It is as if Anthony has been looking after his sister and saving us from more heartache.”...

    Ashleigh was born on September 20 and was healthy and well except for being born with clubfoot meaning she has had to wear casts for the first months of her life.

    Jenna explains: “Because of the restricted space in the sac due to losing the waters, Ashleigh was squashed up and as a result she has talipes, which is also known as clubfoot.”

    “She has been wearing casts on her legs but they will hopefully come off in a few weeks.”

    “But for this to be the only thing wrong when she only had a one in a million chance of surviving is amazing.”