Leukodystrophy Conference Impressions

On June 16th I attended the conference Leukodystrophy: Current, Novel, and Future Therapies, hosted by McGill University Children’s Hospital and Dr. Geneviève Bernard in Montréal, Quebec. It was a busy day, with updates and information about a number of leukodystrophies, including PMD. There were a wide variety of parents and children in attendance, about 100 in all, from many states and provinces. Doctors and researchers presented both in person and via video.

Dr. Keith Van Haren, of Stanford, opened the day with a general discussion of supportive therapies for children. He noted the use of Cystic Fibrosis as a model for care, with specialized care centers and treatment targeting symptoms making a huge difference in both quality of life and improved longevity. He stressed the use of specific therapeutic interventions for each unique leukodystrophy, many of which have similarities that can be applied to care. Key among those treatments are emotional and social supports. He also emphatically commented that caregiver health is essential to the care and survivability of children. He urged care for siblings, who can sometimes feel neglected, as well as staying in touch with communities of support within each leukodystrophy.

The next presenter, Dr. Laura Adang of Children’s Hospital of Philadelphia (and a colleague of Dr. Adeline Verderver), spoke about advances in care and some novel therapies that are either available, or may soon be. She talked about some genetic background information, such as the structure of DNA and the various forms of RNA and how genetic material could potentially be manipulated for treatment. Much of this remains theoretical, though she did note the work being done with CRISPR/CAS9 was very promising. (Interestingly, she did not know about Dr. Paul Tesar’s work in this area, and felt that these therapies are perhaps ten years away.) Dr. Adang also commented on enzyme replacement therapy and bone marrow transplantation for use with some leukodystrophies (though not PMD). Delivery systems and the ability to target the many genetic “errors” would be an important consideration in developing treatments. In a private discussion afterward, she said that she thought work being done with Multiple Sclerosis on myelin repair would be something for the PMD community to keep a close eye on. She also was adamant that a natural history study would be essential for the PMD community in order to move our kids toward potential treatment trials down the road. Dr. Adang was a very engaging speaker and was extremely approachable from a parent perspective.

Also from CHOP, Dr. Adeline Vanderver spoke about Aicardi-Goutières Syndrome, H-ABC, and TUBB-4a, all of which are hypomyelinating disorders. She talked about work being done to examine the effects of different mutations on oligodendrocytes (those cells which produce myelin in the Central Nervous System). I think most importantly she stressed the absolute need for a (retrospective) natural history study in order for families to be ready to take part in any developing treatments in the present and in the future. Without this, children are not identified and in a
controlled system that will be available for the agency or research team conducting trials specific to a leukodystrophy (like PMD). I found this to be the most compelling and critical take-away from her presentation.

Dr. John Mitchell of McGill University talked about lysosomal storage disease treatment and providing therapies for orphan diseases generally. He spoke at length about enzyme replacement therapy, and somewhat less about gene editing. He added that rare diseases are certainly impacted by funding shortfalls and a lack of research. Finding therapies that can be applied generally across a range of similar disorders instead of targeting one specific genetic mutation within a disorder (like PMD) would probably be most useful.

Presenting on the possible uses of nanotherapy, Dr. Ali Fatemi from Johns Hopkins talked about researchers often knowing the molecular level fault in many leukodystrophies, but that providing specific drug-based therapies was a challenge. He reviewed the use of dendringers (2-10 nanometers) as a “carrier molecule” to target drug delivery to the CNS. He explored the difficulties of breaching the blood-brain barrier (BBB) and getting targeted therapy past astrocytes. He also spoke of polyamidoamin use as a delivery system because it is “multifunctional, adaptable, and targetable”. Much of his work was centered around adrenoleukodystrophy (ALD) and others with neuroinflammation.

Dr. Florian Eichler of Massachusetts General Hospital and Harvard Medical School also talked regarding ALD, but shared therapies based on bone marrow transplantation and gene therapy. He was a colleague of the late Dr. Hugo Moser’s. Dr. Eichler was also very open to talking with families, and he and I spoke about my son and treatments for older kids with PMD. We bemoaned the proprietary nature of many therapies and a lack of shared information due to funding and sponsorship. He mentioned that he currently follows three boys with PMD in his clinic at MGH. Dr. Eichler also voiced very strong support for conducting a natural history study (there is a definite theme here among leading researchers!)

After lunch, Dr. Tony Rupar provided information on Metachromatic Leukodystrophy (MLD), another of the lysosomal storage disorders. He spoke about potential genetic therapy for this. He also talked about newborn screening for more of the leukodystrophies, and how this was essential to getting early treatment, especially since early treatment could limit or slow the progression of some disorders.

The host of the conference, Dr. Geneviève Bernard of MUCH discussed future therapeutic strategies for hypomyelinating disorders. While she also gave us some background genetic information on genetic structures and detecting hypomyelination with currently used T1 and T2 weighted MRI, she also provided information on Antisense Oligonucleotide Therapy (ASO) to prevent mutated protein (presumably including PLP1) from affecting myelin. She specifically mentioned PMD as the most common in a group of about 15 conditions. She reviewed stem cell transplantation in hopes of achieving remyelination and clinical improvement. She talked about both Oligodendrocyte Progenitor Cells (OPCs) and Human Neural Stem Cells. She noted the recent Phase One trial, but said that there were still many questions regarding this potential treatment. The study demonstrated that the technique and stem cells used were safe, but that efficacy was unclear at this point. As most other presenters before her had done, she stressed the need for a natural history study as a necessary precursor for future PMD therapies.

Lastly, Dr. Nancy Braverman of MUCH spoke about peroxisome biogenesis disorders such as Zellweger Spectrum Disorder and RCDP Spectrum. She spoke about developing mouse models, drug screening platforms, and testing candidate therapies for these disorders. She is, of course, another strong proponent of natural history studies.

The conference was really a terrific event for the Foundation to be present at. We were acknowledged by Dr. Bernard and others, and sincerely thanked for our sponsorship. One of my biggest takeaways was the need for a natural history study of PMD-affected children. The PMD Foundation is currently working on developing a Natural History study for just this reason. In addition to meeting a number of leading researchers and doctors working hard for treatments for our kids, I also made several connections with families. I was able to employ some very rusty French to talk with some Québécois parents as well. Unfortunately I could not stay for the entire dinner event following the day’s presentations, but all in all it was a great experience! I would heartily encourage members of the foundation to seek out opportunities like this!

Cato the Elder: Carthage must be destroyed!
PMD Researchers: A Natural History Study must be conducted!

Paul Erena