Table 2.
Overview of approved, orphan drug designations, off-labeled therapies for treating lysosomal storage disorders, and examples of some products under development with an orphan drug designation.
| LSDs | Therapeutic agent | Type/Current status | Evidence of CNS penetration |
|---|---|---|---|
| Gaucher disease (GD) | Imiglucerase (Cerezyme) | ERT-IV (produced in CHO cells)/approved* |
None |
| Velaglucerase (VPRIV) | ERT-IV (produced in human cells)/approved* |
None | |
| Taliglucerase (Elelyso) | ERT-IV(produced in plant cells)/approved** | None | |
| miglustat (Zavesca) | SRT/approved* | None | |
| eliglustat (Cerdelga) | SRT/approved | None | |
| ambroxol | PC/off-labeled use neuronopathic forms of GD | Myoclonic epilepsy and cognition improvement; decreased CSF glucoSPG (Narita et al., 2016; Pawlinski et al., 2016; Charkhand et al., 2019; Kim et al., 2020) | |
| Fabry Disease | agalsidase beta (Fabrazyme) | ERT-IV (produced in CHO cells)/approved* |
None |
| agalsidase alfa (Replagal) | ERT-IV (produced in human cells)/approved** |
None | |
| migalastat (Galafold) | PC/approved* | None | |
| MPS-I | Laronidase (Aldurazyme) | ERT-IV(produced in CHO cells)/approved | None |
| HSCT | Cell therapy/approved | Efficacious on neuronopathic MPS-I (Prasad and Kurtzberg, 2010a,b; De Ru et al., 2011) | |
| Fusion-ERT | HIRMAb-IDUA-IV#/ODD | Preliminary evidence in small and short clinical studies (Giugliani et al., 2018)/ODD | |
| MPS-II | Idursulfase (Elaprase) | ERT-IV (produced in human cells)/approved* |
None |
| Idursulfase (Elaprase) | ERT-IT (produced in human cells)/ODD |
Mild effects/ODD (Muenzer et al., 2016) | |
| Idursulfase (Elaprase) | ERT/ODD | Mild improvement spinal cord compressions/ODD | |
| MPS-IIIA | Sulfamidase | ERT-IT/ODD | Decline in HS in CSF/ no change in neuro endpoints/ODD |
| LYS-SAF302 (Lysogene/Sarepta Therap.) |
IV-GT (systemic) LYS-SAF302 |
No results from clinical trials NCT03612869 |
|
| scAAV9.U1a.hSGSH (Abeona Therap) |
IV-GT (systemic) scAAV9.U1a.hSGSH |
No results from clinical trials NCT02716246 |
|
| Ex vivo HSCT | CD34+-Lenti-transduced (SGSH) | No results from clinical trials NCT04201405 |
|
| MPS-IIIB | SBC-103(rhNAGLU) (Alexion Pharm.) |
ERT-IV | Negative results (Whitley et al., 2019) |
| NAGLU–IGF2 fusion protein | NAGLU–IGF2 fusion protein -IV#/ODD | No results from clinical trials (Prill et al., 2019) |
|
| rAAV9.CMV.hNAGLU | IV-GT (systemic) -rAAV9.CMV.hNAGLU/ODD | No results from clinical trials NCT03315182 |
|
| rAAV2/5-hNAGLU (UniQure Biopharma B.V.) | IT-GT (local) rAAV2/5-hNAGLU |
No results from clinical trials NCT03300453 |
|
| MPS-IVA Morquio Synd. |
elosulfase (Vimizim), | ERT-IV (produced in CHO cells)/approved* |
None |
| MPS-VI Maroteaux-Lamy |
galsulfase (Naglazyme) | ERT-IV (produced in CHO cells)/approved* |
None |
| MPS-VII Sly syndrome |
vestronidase alfa (Mepsevii) | ERT-IV (produced in CHO cells)/approved* |
None |
| Pompe Disease GSD-II |
alglucosidase alfa (Lumizyme) | ERT-IV (produced in CHO cells)/approved* |
None |
| alglucosidase alfa (Myozyme) | ERT-IV (produced in CHO cells)/approved** |
None | |
| avalglucosidase alfa, (neo-GAA; ATB200; Amicus)+ AT2221 (miglustat) | ERT-IV (rhGAA-ATB200)/PC (AT2221)/ODD | None (Xu et al., 2019) | |
| Metachromatic Leukodystrophy | Ex vivo HSCT | GT-Lenti-transduced (ARSA)/ODD | Stabilization of neurocognition and white-matter signal in brain MRI studies (Sessa et al., 2016) |
| Globoid-cell leukodystrophy (GLD), Krabbe disease | HSCT | Cell therapy/approved | HSCT at <30 days of age, improvements in mobility, speech, oropharyngeal function (Allewelt et al., 2018) |
| Lysosomal acid lipase deficiency (Wolman disease/cholesteryl ester storage disease) |
Sebelipase (Kanuma) | ERT-IV (produced in egg white–genetically modified chicken)/Approved* |
None |
| Neuronal ceroid lipofuscinosis type 2 |
Cerliponase (Brineura) | ERT-IT (produced in recombinant CHO cells)/Approved* | Reduce progression of neuro-cognitive decline (Markham, 2017; Schulz et al., 2018) |
| Niemann–Pick disease type B (Acid sphingomyelinase deficiency) |
olipudase alfa | ERT-IV (produced in CHO cells) | Not yet observed (Wasserstein et al., 2018) |
| Niemann–Pick disease type C | miglustat (Zavesca) |
SRT (oral) | HSEM velocity; improvement in swallowing capacity, auditory acuity, and a slower deterioration |
| Vorinostat | HDAC inhibitor/off-labeled use neuronopathic forms of GD | None NCT02124083 |
|
| 2-Hydroxypropyl-β-Cyclodextrin (VTS-270) |
IT-VTS-270 | Stable but slower-than-average Cognitive Scales (Farmer et al., 2019) | |
| α-Mannosidosis | velmanase alfa/(Lamzede) | ERT-IV (produced in CHO cells/approved) | None (Borgwardt et al., 2018) |
*
Approved in Europe, USA, and other countries;
**
Approved in USA, Brazil and Canada;
***Approved in Europe. CHO, Chinese Hamster Ovary, CHO cells; enzyme replacement therapy; ERT, enzyme replacement therapy; glucoSPG, glucosylsphingosine; GSD, glycogen storage disease; GT, gene therapy; HIRMAb, human insulin receptor monoclonal antibody; HSEM, horizontal saccadic eye movement; HSCs, hematopoietic stem cells; HSCT, hematopoietic stem cell therapy; HSP, heat shock protein; IV, intravenous (systemic); IT, intra-thecal (local); MPS, mucopolysaccharidosis; NAGLU, alpha-N-acetylglucosaminidase; ODD, orphan drug designation; SRT, substrate reduction therapy; PC, pharmacological chaperones.