Myelin Project

11/92 “Shaking Pups ”. Remyelination w/in a 3cm radius from implant site. ( Oligodendrocytes and its’ precursors)

12/96- 2 series of human glial cells are cultured providing a continuous supply of transplantable myelin-forming cells

1/97- Oligodendrocytes & precursors have the greatest capacity for myelination following grafting, although cells of neuronal origin may also be used

1/97- Progesterone promotes re-myelination by activating the genes that control the synthesis of important myelin proteins- but side effects on reproductive functions

Amgen - Shaker/ Shiverer rats, newly developed mouse model .

Monkey Schwann cells into animal optic gene did not work Other researches used Schwann cells & astrocytes mixture to remyelinate rats

11/98 - Phase I human tria l for transplanting Schwann cells in CNS of 5 MS patients, but must demonstrate that it is not harmful in monkeys first

Oecs (olfactory ensheathing cells) from pigs into demyelinated & monkeys significant remyelination

6/11/2000-Michaela Odone dies; Lorenzo 22 yrs old

12/2000- OECs can remyelinate axons of CNS in rat model

Yale has second thoughts about the already approved Phase I human trial . It was supposed to start 9/2000, but Yale decides to have an independent researcher give final approval.

7/2001- Phase I finally starts ! Schwann cells (1 million) transplanted into a 53 year old woman suffering from progressive MS. Taken from her own nerve and injected into the right frontal lobe of the brain. (Reminder: Phase I trial is meant to prove safety)

4/2003- Patient #3 has Schwann cells injected .

Brain stem cells injected into the blood stream of MS model mice can find their way to the CNS and begin remyelinating the lesions.

5/29/03- Lorenzo turns 25.

10/23/03 Highlights from the 14 th annual myelin project meeting: Marmoset trial- Played himself in the testing the ability of movie ☺☺☺ transplanted human neural stem cells to repair myelin damage. Follow-up studies to “Lorenzo’s Oil”: 2 different studies confirms “that the Oil is effective in delaying the onset of ALD in boys w/o symptoms who started the therapy under the age of six.”

2004- Working on remyelination . 2 main areas: 1.) transplantation of myelin forming cells. Experiments with a.) stem cells b.) Schwann cells c.) Olfactory ensheathing cells (OEC’s)

Working on controlling blood levels of fat with pharmaceuticals: a.) progesterone derivative b.) statins w/ interferon c.) Lipitor plus (relief in 45 MS patients)

5/04- Lorenzo turns 26

6/7/04- no harmful side effects seen in marmosets due to transplanted neural stem cells or from the immune-suppressing drugs OPC’s (oligodendrocyte progenitor cells) given to rats traveled 23mm in both directions and produced extensive remyelination .

6/05 - conclusion of 13 year study on the effectiveness of Lorenzo’s Oil in preventing symptoms in 89 ALD boys .

Late 05- Development of a new method that makes it more likely that infants will be able to be screened for ALD. Working to perfect the technique .

9/06 Summer update for the myelin project: Robin Franklin; (Cambridge,UK)- observed that aging brains don’t clean up damaged myelin well, which inhibits remyelination . Macrophages are normally in charge of this clean-up. Hypothesized that promoting inflammation (increasing macrophages)would allow transplanted precursor cells to be more effective. Did one transplant and found hypothesis to be true. Jeffrey Kocsis (Yale)- transplants OEC & Schwann cells into injured spinal cord. Result: axonal regeneration and axons formed Nodes of Ranvier with proper sodium and potassium channels. Increase in function noted. Also used an IV injection of gene-modified human mesenchymal stem cells (hMSCS) in a cerebral lesion which resulted in a functional increase. Johannes Berger (Medical Univ. of Vienna brain research Inst .)- gene for defective protein in ALD boys is ABCD1. There’s a very closely related gene that makes a similar protein (ALDRP- adrenoleukodystrophy related protein) called ABCD2. An increase in ALDRP can substitute for the loss of ALDP. Perhaps this could be an alternative for a future therapy. The promoter for ABCD2 is a sequence just prior to the gene but this promoter also affects many other genes. Work must be done to analyze specific elements of the ABCD2 promoter. Hugo Moser (John Hopkins) aka Dr. Nikolais- Follow-up to 2002 results with 89 boys. Yes, there is a decrease in VLCFAs. Boys who stayed on the diet reduce the risk of ALD by a factor of 2 or more. Growth and cognitive development were normal. No serious side effects. New study with 60 boys is underway to see if positive results are repeatable.

Lorenzo died at his home in Fairfax, Virginia on May 30, 2008, one day after his 30th birthday due to complications of aspiration pneumonia, with his father Augusto and his life long friend Oumouri at his side. [3]

November 2009- Reported in the journal Science: Gene therapy useful in the treatment of ALD ! 2 boys tested and both show healthy cells 2 years after gene therapy. Gene is delivered via an HIV-derived virus vector. This vector is significant b/c it infects dividing cells, so their derivitives should have the proper genome from that point on. This therapy is important for boys who could not get a bone marrow transplant due to a lack of donor (no match). The results of the gene therapy are similar to that of bone marrow transplants: remyelination (not 100%) which leads to increased neurological function. Gene therapy does carry the risk that the biology of the cells is disrupted and the patients end up with leukemia. gene therapy science daily.com In the study, blood stem cells were removed from the patients and genetically corrected in the lab, using a lentiviral vector to introduce a working copy of the ALD gene into the cells. The modified cells were then infused back into the patients' after they had received a treatment that destroyed their bone marrow . Two years later, healthy ALD proteins were still detectable in both patients' blood cells . Encouragingly, both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants. The healthy ALD protein was expressed in about 15 percent of blood cells, yet surprisingly this low level was sufficient to slow brain disease in ALD. "This percentage of correction will not be sufficient for all diseases," warns Aubourg. "There is a lot of work to be done to make this gene therapy vector more powerful, less complicated, and less expensive. This is only the beginning," he said.

New Data from Adrenoleukodystrophy (ALD) Pilot Study Presented at American Society of Gene and Cell Therapy Show Three-Year Disease Stabilization of Patients

CAMBRIDGE, Mass. & WASHINGTON--(BUSINESS WIRE)-- May 20, 2010 - Nathalie Cartier-Lacave, M.D., study investigator and a director of research at the National Institute of Health and Medical Research in France (INSERM), and collaborator of Genetix Pharmaceuticals, Inc., today presented additional data from a pilot study treating X-linked adrenoleukodystrophy (ALD) at the American Society of Gene and Cell Therapy's 13 th Annual Meeting. The findings demonstrate continued stable expression of ALD protein and disease stabilization at three years in two ALD patients. Initial data on a third patient show stable expression of the protein at 20 months; however, current data are insufficient to determine disease stabilization. Genetix, an emerging leader in developing breakthrough gene therapies for severe genetic disorders, plans to initiate larger clinical studies in ALD in both the United States and Europe in 2011.

2010 News from the Laboratory:

• Dr. Jeff Kocsis (Yale University) has shown that mesenchymal stem cells derived from adult human bone marrow when transplanted into experimental demyelinating lesions, produce a significant improvement in functional outcome. They do this by stimulating new myelin formation.

• In Milan, Italy Dr. Luigi Naldini ( San Raffaele TelethonInstitute for GeneTherapy ) and his group have been working on gene therapy for the treatment of two severe leukodystrophies, metachromatic leukodystrophy and Krabbe’s disease. Their work is based on using lentiviral vectors in combination with hematopoietic stem cells and is heading into Phase I/II clinical trials.

• Also in Milan, Dr. Gianvito Martino’s lab (San Raffaele Hospital) has been working in the field of stem cell biology, particularly neural stem cells. They have shown that these cells, when transplanted into models of MS, have marked effects on the immune system and help protect against neurodegeneration. The goal is to take this approach into clinical trials.

• Dr. Robin Franklin’s group at the University of Cambridge have been working on the idea that the brain contains a population of endogenous stem cells or progenitors that can be recruited to become myelinating cells in MS, and possibly other myelin disorders. They have identified some key molecules that might be used in future clinical trials, to promote ‘host’ repair.

• Dr. Wolfgang Brück (Universityof Göttingen ) has been studying the immunopathology of MS lesions in attempts to unravel the mechanisms behind endogenous remyelination . It appears that in MS lesions, sufficient myelin-forming precursor cells are present but they do not differentiate into mature cells.

• In Paris, Dr. Anne Baron Van Evercooren (L' hopital de la Salpetriere) and her colleagues have been involved in studying remyelination, both by transplanted cells (exogenous) and by host cells (endogenous). They have worked both with myelinating cells from the peripheral nervous system and central nervous system. They have shown activation of neural stem cells from key areas of the CNS in animal models and in the brain of MS patients. They have also evaluated the biological properties of human fetal neural precursors on transplantation into animals. • Dr. Ian Duncan at the University of Wisconsin-Madison and his colleagues have worked extensively on the cells that could be used for transplant repair including human embryonic and neural stem cells. Most recently they have provided the first definitive proof that widespread remyelination restores function, confirming that this is an important therapeutic strategy.

Clinical trial underway to evaluate whole genome sequencing https://clinicaltrials.gov/ct2/show/NCT01087320 h

The Myelin Project aims to accelerate research on myelin repair. Myelin can be destroyed by hereditary neurodegenerative disorders such as the leukodystrophies, and by other diseases such as multiple sclerosis. All together, demyelinating diseases affect more than two million people worldwide.

The Myelin Project headquarters has recently moved from Amarillo, Texas where it was housed on the Texas Tech University Health Sciences Center campus in the Laura W. Bush Institute for Women's Research to Pacific Palisades.

Published: October 20th, 2011 | By: Journal of Neuroinflammation

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients. Read more...

2012 - MSC- mesenchymal stem cell transplants show possibilities for remyelination in MS patients. Scar tissue must be removed from the lesion sites in order for remyelination to occur.

2013 - microglial cells are being used to try to clean up the scar tissue in the brain.

2014- AB1559 introduced in CA in January and passed into law Sept. 25 th ☺ CA is the 4 th state to pass such legislation.

Clinical trials at UCLA, Boston Children’s Hospital and the University of Minnesota are currently accepting volunteers for Phase 2/3 clinical trials for ALD gene therapy.

Hospitalhttp://clinicaltrials.gov/ct2/show/NCT01896102?term=ALD- 102&rank=1 http://clinicaltrials.gov/ct2/show/NCT01896102?term=ALD-102&rank=1 2015 - 8/15/2015- “The federal advisory committee for diseases in newborns voted to recommend ALD to the national Newborn Screening List” #SaveTheBoys

ALD gene therapy clinical trials continuing. (see 2013-14)

Whole genome sequencing clinical trial is still accepting applicants (see 2010)

2016 September 2016 California begins newborn screening for ALD!

Remylination experiments continue. Some scientists have been able to turn skin cells into oligodendrocytes .

There is also a drug that has been approved for use in MS patients and helps inhibit enzymes that make harmful fatty acids .

In Germany scientists are experimenting with human growth hormone to promote growth of myelin. Initial results seem promising.

http://www.healthline.com/health/multiple-sclerosis/remyelination-possibilities

Preliminary results to the phase 2/3 gene therapy study :

“On April 20, in Vancouver, Canada, at the annual meeting of the American Academy of Neurology, Cambridge, Massachusetts-based bluebird bio, Inc. announced the preliminary results of its open-label, phase 2/3 gene therapy study . The experimental treatment replaces the lost or deficient ALD protein to help cells break down VLCFAs. The results are not only encouraging but also show the treatment’s promise to avoid complications associated with allogeneic transplant. That is because the experimental therapy is autologous — meaning it uses the patient’s own modified stem cells — negating the need for a donor.

On MRI, 14 out of 17 patients showed stabilization of demyelination and atrophy. ”

https://vector.childrenshospital.org/2016/04/forty-years-waiting-for-a-cure-ald-gene- therapy-trial-shows-early-promise/