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The blood-brain barrier (BBB) is a blessing and a curse. A semipermeable membrane that excludes toxins and pathogens from the central nervous system while admitting nutrients and other essential molecules, the barrier is vital to protecting the brain’s delicate circuitry. Unfortunately, this also means that the BBB keeps most potential therapeutic drugs out as well.[i] This property magnifies the challenge of developing treatments for a wide range of diseases affecting the brain, from Gaucher disease type 3 to Hunter syndrome, to migraines, to cancer.

At this month’s WORLDSymposium™ in San Diego, experts will be meeting to discuss the newest research for lysosomal disorders, a family of about 50 rare diseases caused by mutations in a single gene that lead to the accumulation of materials in cells that can be toxic. Many of these genetic mutations disable an enzyme that is responsible for degrading or transforming a specific type of metabolite. Depending on how toxic the buildup of the metabolite is, how fast it accumulates, and where it accumulates, these diseases can cause symptoms across multiple organs — including the brain. It is estimated that at least 70 percent of lysosomal disorders have a CNS component.[ii]

An Incomplete Solution

Over the last two decades, enzyme replacement therapy (ERT) has dramatically improved the health and prolonged the lives of people with lysosomal disorders. As the name implies, ERT aims to replace the missing enzyme through intravenous infusions typically every two weeks. But ERT requires lifelong, regular treatment to continually renew the supply of enzymes as they are rapidly broken down in the body. Moreover, ERT may not halt the overall progression of disease and patients may eventually require organ transplants or other intensive procedures. However, a critical drawback of ERT for many lysosomal disorders is its inability to cross the BBB.

That deficiency in lysosomal disorders such as Hunter syndrome and Pompe disease means that ERT cannot address serious neurological symptoms like developmental delays, memory loss and seizures.[iii] Similarly, ERT likely cannot reduce the up to 20-fold increase in risk for Parkinson’s disease that is associated with Gaucher disease[iv]. The degree of impact that lysosomal disorders have on the central nervous system was not fully appreciated until the availability of ERT showed that these symptoms were not secondary results of damage to other organs, but directly caused by the buildup of metabolic products in the brain.[v]

Gene Therapy’s Promise

Gene therapy has the potential to fill this gap by offering a one-time treatment that continuously replaces the missing enzyme in every part of the body, including the brain. One such approach that can cross the BBB uses the patient’s own hematopoietic stem cells, which are modified in the lab to incorporate the genetic instructions for the missing enzyme into their genomes and then infused back into the patient.

Once engrafted, these cells can differentiate into different hematopoietic cell types, including microglia-like cells within the brain. In animal experiments, data have shown widespread engraftment of genetically modified microglia-like cells throughout the brain that can produce the otherwise missing protein.[vi] Combined with the observations from researchers in Europe who have tested unmodified hematopoietic stem cell transplants as a treatment for lysosomal disorders,[vii] this research strongly suggests that gene therapy targeting hematopoietic stem cells has the potential to address CNS disease manifestations for many patients.

Into the Clinic

Multiple ongoing clinical trials are currently looking at the potential of gene therapies for lysosomal disorders. In addition to two ongoing clinical trials for cystinosis[viii] and Gaucher disease type 1, AVROBIO expects to initiate clinical trials next year in Gaucher disease type 3, Hunter syndrome[ix] and Pompe disease. We are greatly encouraged by the prospect that more people living with lysosomal disorders may soon receive these investigational treatments with the potential to fill significant gaps in their current standard of care.

Learn more about clinical trials being conducted around the world and find out about AVROBIO’s work in lysosomal disorders.


[i] Pardridge W. M. (2006) Blood-brain barrier delivery. Drug Discovery Today 12: 54–61

[ii] Wraith J.E. (2004) Clinical aspects and diagnosis. In F.M. Platt, S.U. Walkley (Eds.), Lysosomal Disorders of the Brain, Oxford University Press, Oxford, pp. 50-77

[iii] Edelman, M.J. and G.H.B. Maegawa (2020) CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges. Front. Mol. Biosci. 7:559804. doi: 10.3389/fmolb.2020.559804

[iv] Riboldi, G.M. and A.B. Di Fonzo (2019) GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches. Cells. 8(4): 364 doi: 10.3390/cells8040364

[v] Trauner, D.A. (2017) Neurocognitive Complications of Cystinosis. The Journal of Pediatrics. 183: S15-S18

[vi] Ellison, S. et al. (2022) Enhanced transduction and immunophenotyping demonstrates safety and efficacy of haematopoietic stem cell gene therapy for Mucopolysaccharidosis II using an IDS.ApoEII brain targeted therapy. WORLD Symposium. Presented February 8, 2022

[vii] Wolf, N.I. et al. (2020) Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann. Clin. Transl. Neurol. 7(2): 169-180 doi: 10.1002/acn3.50975

[viii] Collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04 is funded in part by grants to UCSD from the California Institute for Regenerative Medicine (CIRM), Cystinosis Research Foundation (CRF) and National Institutes of Health (NIH)

[ix] Developed by our collaborators at the University of Manchester, UK