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Overcoming the blood-brain barrier: New approaches to treating CNS complications of lysosomal disorders

Former President & CEO

Geoff MacKay | Former President & CEO

My colleagues and I returned last month from the WORLDSymposium, a bustling scientific conference devoted exclusively to the dozens of rare genetic diseases classified as lysosomal disorders. We heard inspiring stories from families and advocates and reviewed the latest research from around the world. It is impossible not to come away optimistic for the future of treating — and perhaps even curing — these debilitating diseases.

One unmistakable theme at the conference: how to best treat symptoms arising in the central nervous system (CNS). This has long been a major challenge. The standard of care for many lysosomal disorders are enzyme replacement therapies (ERT), which slow the progression of disease but cannot effectively cross the blood-brain barrier, an intricate web of protective tissue that selectively prevents many substances – including, unfortunately, approved ERTs – from entering the brain.

As we saw at the conference, however, the blood-brain barrier is starting to yield to scientific advances. New investigational approaches have the potential to ferry therapeutic proteins into the brain. And that might mean a revolution in care for patients and families living with lysosomal disorders.

The potential improvements over standard of care are most obvious in lysosomal disorders with a strong neurocognitive component, such as metachromatic leukodystrophy (MLD), a devastating and fatal disorder in which young children progressively lose motor and cognitive skills. However, researchers are increasingly recognizing and documenting a strong CNS component in other lysosomal disorders as well.

Consider Fabry disease, a rare genetic disease that can affect many parts of the body including the kidneys, heart, and skin. Much of the focus in recent decades has been on the progression of kidney and cardiac damage in people living with Fabry. But people with Fabry are also known to be at an increased risk of recurrent strokes and transient ischemic attacks, and some patients experience a blurring of their cognitive abilities, often dubbed “Fabry fog.” The scientific community is now beginning to understand the root of these complications. A systematic literature review from 2018 found that lesions in the white matter of the brain were present in 46 percent of people with Fabry (581 out of 1276 patients studied).1  The lesions, which are clearly visible on a brain MRI, progressed in a significant number of patients (25 percent) and were associated with risk of stroke. What’s more, progression of these lesions is not slowed by treatment with ERT, the current standard of care.2

To learn more, my colleagues and I have spent considerable time over the past several months talking to physicians who treat people with Fabry. They have each expressed the conviction that there are real and damaging cognitive effects associated with Fabry disease. These effects may have lifelong ramifications, including making it more challenging for individuals with Fabry to complete higher education and hold down jobs.

Gaucher disease type 1 is another lysosomal disorder that until recently was not considered to involve the central nervous system. Now, however, we believe that there is an association with Parkinson’s disease. Indeed, the adjusted lifetime relative risk of Gaucher type 1 patients developing Parkinson’s may be more than 20 times greater than the general population.3 Research presented at the WORLDSymposium also suggested that people with Gaucher type 1 may endure a range of additional neurological complications, including neuropathic pain and hyposomia (impaired ability to smell).

How are scientists trying to address these CNS complications? The WORLDSymposium offered glimpses into several promising approaches:

  • Denali Therapeutics and JCR Pharmaceuticals each shared data supporting investigational therapies that fuse an enzyme designed to treat Hunter syndrome (also known as mucopolysaccharidosis type II) with a protein capable of crossing the blood-brain barrier.
  • Sanofi Genzyme presented data from a study of an existing chronic injectable ERT combined with venglustat, an oral investigational small molecule therapy designed to inhibit a key enzyme (glucosylceramide synthase) in patients with Gaucher disease type 3. The combination therapy appears to cross the blood-brain barrier and reduce toxic substrate in the cerebrospinal fluid, thus potentially addressing neurological symptoms.
  • A researcher from the Vall d’Hebron Research Institute presented research supporting the use of natural cellular transporters – extracellular vesicles (EVs) – as a delivery mechanism for enzymes. They were seen to deliver enzyme into lysosomes across a variety of cell types, and in mouse models brain distribution of the EV-ferried enzyme was clearly seen.
  • Orchard Therapeutics presented promising data from young children with MLD who have been treated with the investigational therapy OTL-200, an investigational ex vivo, lentiviral gene therapy.4 The children, many of whom had older siblings who died from MLD, are retaining cognition and motor skills at time points when the natural history of the disease would suggest they would otherwise be regressing; treatment effects are also observed on brain images. This, of course, is wonderful news for patients and families.

Along with clinical updates from our Fabry and cystinosis trials,  AVROBIO presented preclinical data at the WORLDSymposium suggesting widespread engraftment in the brain of treated cells carrying a therapeutic gene.

WORLD slide - preclinical microglia data 

That engraftment took place in brain regions critical for cognitive, motor, olfactory and visual function. We also found that the engrafted cells carrying the therapeutic gene looked and acted very much like microglia cells, which play a critical role in maintaining healthy brain function. We are actively working to advance these findings.

The team at AVRO is exceptionally proud to be among the scientific leaders focused on this critical field of research. ERTs have saved the lives of countless people with lysosomal disorders in the past 30 years, and we are all profoundly grateful. We want to build on this progress with a new generation of therapies that can drive expression of the functional protein patients need not just throughout the body, but throughout the brain as well.

As the presentations at the WORLDSymposium demonstrated, we believe we can get there. And this is not some pipe dream. As a scientific community, our hope is that we are well on our way.


  1. Molecular Genetics and Metabolism 1 25 (2018) 205-16
  2. Neurology, 2018;91:e1413-e1422. doi:10.1212/WNL.0000000000006316
  3. Blood Cells, Molecules, and Diseases, Volume 46, Issue 1, 15 January 2011, Pages 95-102
  4. Orchard Therapeutics Presents Data from OTL-200 in Patients with Metachromatic Leukodystrophy Using Cryopreservation


This blog contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding AVROBIO’s business strategy, prospective products and goals, the therapeutic potential of our preclinical and clinical product candidates, and the anticipated benefits of our gene therapy platform. Any such statements in this blog that are not statements of historical fact may be deemed to be forward-looking statements based on current expectations, estimates and projections and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. For a discussion of these and other risks and uncertainties, see the section entitled “Risk Factors” in AVROBIO’s most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission.