Florian Eichler - Center for Genomic Medicine

Florian Eichler, a neurologist, leverages the biology of single gene disorders affecting the nervous system to develop treatments for leukodystrophies and hereditary neuropathies. Among his scientific contributions, Dr. Eichler has discovered neurotoxic sphingolipids underlying hereditary sensory neuropathy type 1 (HSAN1) and unraveled mechanisms of brain demyelination in leukodystrophies. As a clinician he has performed a first gene therapy trial for adrenoleukodystrophy as well as a L-serine supplementation trial in HSAN1. As Director of the Center for Rare Neurological Diseases he aims to accelerate progress and treatment for rare conditions by understanding unmet, identifying knowledge gaps and creating partnerships.

Questions being addressed in the lab

How do single disease-causing genes lead to progressive neurodegeneration?
Does selective vulnerability inform what cell types should be targeted during treatment?
What strategies can accelerate treatment development for devastating rare disorders of the nervous system?

Projects underway to answer these questions

Our group has taken research from bench to bedside by finding a dietary change that helps patients with a rare familial neuropathy. We discovered that the mutations causing HSAN1 induce a shift in the substrate preference from serine to alanine thereby forming a class of neurotoxic deoxysphingolipids. Based on the mechanism of this lipid generation, we hypothesized that L-serine supplementation would prove to be beneficial and were able to prove this in mice and humans with HSAN1. In a first trial of this disorder (NCT01733407), patients on L-serine experienced significant improvement on a neuropathy scale and experienced less sharp pain compared to the placebo group.
We are leading an international clinical trial that is performing ex vivo lentiviral gene therapy in childhood cerebral adrenoleukodystrophy (NCT01896102). We were also the first to show the ability of an adeno-associated virus to target the intracellular peroxisomal membrane and lower very long chain fatty acids. This was critical proof of concept to justify developing an in vivo gene therapy for adrenomyeloneuropathy, the most common metabolic hereditary spastic paraplegia.
Using both imaging tools and post mortem pathological analysis, our group has contributed to the understanding of disease progression and the pathophysiology of adrenoleukodystrophy. We have defined microglial dysfunction in the disease as distinct from that of other demyelinating disorders. More recently, the lab has discovered that the disease-causing gene ABCD1 has a specific role in maintaining barrier function in brain microvascular endothelial cells.

Answers Found

STARBEAM (ALD-102) (NCT01896102): We completed a single-arm, open-label, phase 2/3 safety and efficacy trial of Lenti-D™, an investigational gene therapeutic approach utilizing a lentiviral vector encoding the ALD protein to transduce autologous hematopoietic stem cells that aims to restore functional protein expression in microglia and halt disease progression in childhood cerebral adrenoleukodystrophy.
In our overall effort to advance treatments for adrenoleukodystrophy, we founded the consortium ALD Connect, a research network that spans 7 academic institutions and 5 patient advocacy organizations. The consortium was awarded a contract from PCORI and received the Global Genes Award in 2014. It has brought together stakeholders from academia, patient advocacy and industry and thereby accelerated trial development in this rare condition.
Our group has discovered how the enzyme serine palmitoyltransferase regulates mechanisms of sensory neuron and axonal growth. We found that the mutant enzyme preferentially uses L-alanine over its canonical substrate L-serine, and also investigated the effects of substrate availability on dorsal root ganglia neurons. Supplementation with L-serine or removal of L-alanine independently restored normal growth patterns in mutant transgenic mice.