Looking back and moving forward: What’s next for lysosomal storage disorders

Britt Johnson Ph.D., FACMG, Medical Director of Metabolic Genetics

As the 16th annual WORLDSymposium on lysosomal storage disorders (LSDs) is this week, I find myself reflecting on the many advancements that have been made since I started my first clinical genetics fellowship just 10 years ago. 

I am excited to join the unique mix of researchers, clinicians, patient advocacy groups, and biopharma companies for four days in Orlando, Florida. This group of experts is interested in improving care and outcomes for patients with LSDs by learning and sharing the latest research and advancements in the field.

LSDs are a heterogenous group of progressive multisystemic disorders with high morbidity and mortality that arise due to inherited defects in lysosomal function. To date, over 55 LSDs have been discovered. Individually, LSDs are rare, but collectively they have an estimated incidence of 1 in 5,000.1 Newer studies from newborn screening suggest that the incidence may even be higher than original estimates, making it all the more critical to improve care and outcomes for patients.2,3 All LSDs are characterized by accumulation or abnormal storage of macromolecules in the lysosomes over time. The underlying defects are most often due to deficiencies of the lysosomal acid hydrolases, but they can also be due to defects in the lysosomal transporters and membrane associated proteins.

Most LSDs fall on a phenotypic spectrum that ranges from severe symptoms that begin in childhood to milder adult-onset forms of the disease. LSDs are difficult to diagnose because symptoms are broad, affect multiple organ systems, and often build gradually. As a result, individuals with LSDs often see a wide range of medical specialists such as pediatricians, cardiologists, neurologists, orthopedists, gastroenterologists, and hepatologists (to name a few) in search of a diagnosis. Clinical genetics is typically considered later into the diagnostic odyssey which can be devastating because LSDs worsen in severity over time. Early diagnosis is crucial for improving prognosis in affected individuals and for preserving neurocognition. Certain therapies like enzyme replacement therapies (ERTs) and substrate reduction therapies (SRTs) can help, but there are many new treatments currently being tested in clinical trials.

Ten years ago, there were six FDA-approved ERTs and only one FDA-approved SRT.4 Now, there are now at least 20 FDA-approved targeted therapies and numerous interventional clinical trials for these disorders.5,6 ERTs replace the enzyme deficiency in a patient using a recombinant enzyme that contains a lysosomal targeting signal. Although ERTs have been successful across multiple LSDs, they do have limitations, particularly for disorders with central nervous system involvement.5 SRTs are oral therapies that inhibit enzymes upstream of the deficient enzyme, thereby reducing the precursor macromolecule substrates that accumulate in the lysosome. Chaperone therapy acts to stabilize the patient’s own deficient enzyme, to increase its function.  

The latest promising advancements in treatments are gene therapy and gene editing, which are currently in clinical trials. These therapies are particularly exciting because they have the potential to greatly reduce or even eliminate the need for continual treatment, effectively “curing” or stopping progression of the disorder. With gene therapy, a normal copy of the defective gene is inserted into a vector which is infused into the patient’s blood, cerebrospinal fluid, or directly into target tissue (in vivo). Cells can then uptake the vector containing the normal copy of the gene and produce the needed enzyme. Alternatively, hematopoietic stem cells can be isolated from the patient, the gene therapy vector can be applied to the cells in culture (ex vivo), and then the vector expressing cells can be infused back into the patient. Preliminary results from the first-ever human gene editing clinical trials for mucopolysaccharidosis (MPS) II and MPS I were a very hot topic at WORLD last year.7 With gene editing, the patient’s mutated gene can be directly edited and corrected or a normal copy can be inserted into the genome of target cells, either in vivo or ex vivo.8 The promise of gene editing is that since the normal gene copy is inserted into the patient’s genome, it could be infused once and wouldn’t be subject to dilution as the patient grows. The preliminary results from these studies have demonstrated that gene editing is a possible therapeutic tool for LSDs and are paving the way for future clinical trials.  

In addition to advancements in therapies, advancements in genetic testing have also occurred in the last 10 years. Large gene panels, enabled by next generation sequencing (NGS), are now routine in molecular diagnostic labs. NGS allows us to sequence many genes at once with lower cost and faster sequencing speeds and higher accuracy than traditional Sanger sequencing.9 In addition, advances in bioinformatic algorithms and NGS processes enable us to detect variants that weren’t traditionally detected by NGS.10,11 At Invitae, this allows us to test for single genes or panels of up to 53 genes for LSDs. 

With all of these approved targeted therapies and interventional clinical trials for LSDs, early diagnosis via genetic testing is even more critical as it is most effective to initiate therapy before irreversible damage occurs. For many patients, one of the barriers to getting genetic testing has always been cost. At Invitae, our mission is to increase access to genetic testing. To help ease the financial burden of testing on LSD patients, and to shorten the diagnostic odyssey, we’ve developed a sponsored testing program that offers testing at no charge to patients suspected of having an LSD. 

So far we’ve tested hundreds of patients through this sponsored testing program and have already helped diagnose a wide variety of disorders––most of which are actionable via an approved therapy or interventional clinical trial! To learn more about the Detect LSDs program, visit here.


1. Lysosomal Storage Disorders. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/lysosomal-storage-disorders. Accessed February 2020.
2. Hopkins PV, et al. JAMA Pediatr. 2018;172(7):696-7. 
3. Burton BK, et al. J Pediatr. 2017;190:130-5.
4. Ratko TA, et al. Enzyme-replacement therapies for lysosomal storage diseases. Technical Briefs, No. 12. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013. 
5. Platt FM, et al. Nat Rev Dis Primers. 2018;4(1):27.
6. Orphan Drug Designations and Approvals. US Food and Drug Administration website. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Accessed February 2020.
7. WORLDSymposiumTM 2019 Program. https://worldsymposia.org/wp-content/uploads/WORLDSymposium-Program-2019.pdf. Accessed February 2020.
8. Poletto E, et al. Int J Mol Sci. 2020;21(2). pii: E500.  
9. Beck TF, et al. Clin Chem. 2016;62(4):647-54.
10. Truty R, et al. Genet Med. 2019;21(1):114-23.
11. Nord AS, et al. BMC Genomics. 2011;12:184.