Update 7/6/2015: LSD company landscape table updated with new details concerning REGENXBIO’s LSD programs.
This week I have been giving some thought to the Sanfilippo B gene therapy program (AMT-110) that uniQure has rights to in-license from Institut Pasteur. With AMT-110 data expected within the next 6 months, I decided it would be prudent to give a brief overview of gene therapy for lysosomal storage diseases, especially with Plasmatech Pharmaceuticals (PTBI) completing their reverse merger with the private gene therapy company Abeona Therapeutics (ABEO) last week.
Lysosomal Storage Disease Overview
Lysosomal storage diseases (LSDs) are inherited metabolic storage diseases characterized by progressive accumulation of undigested materials in the lysosomes of affected cells – a consequence of a genetic defect resulting in missing/improperly functioning digestive enzyme(s). LSDs are an ideal class of disorders to target with gene therapy due to their monogenic nature and clearly defined biology. Further, modest enzymatic activity may be sufficient for clinical efficacy in storage disease with CNS involvement – see Bluebird’s Adrenoleukodystrophy data [1,2]. LSDs with central nervous system (CNS) involvement are the first group of LSDs to be treated with gene therapy most likely because of the poor existing standard of care – limited protein replacement therapy (ERT/SRT) and hematopoietic stem cell transplantation (HSCT). A comparison of the advantages and disadvantages of each therapeutic option for LSDs can be seen below, along with a table of LSDs treated with ERT such as Shire’s (SHPG) Elaprase (idursulfase) and Sanofi/Genzyme’s (SNY) Aldurazyme (lardonidase) :
Protein replacement therapies tend to be ineffective for the CNS disease in LSDs because of their inability to cross the blood-brain barrier. In order to promote transgene expression in the CNS, in-vivo gene therapy for LSDs with CNS involvement primarily rely on three routes of administration: intravenous delivery (IV), CSF injection, or direct injection into the brain. In addition, ex-vivo gene therapy in these indications rests on traditional HSCT with modified stem cells, resulting in modified progenitor cells migrating to the CNS. There is, however, clinical proof-of-concept data in LSD for CNS involvement in both in-vivo and ex-vivo gene therapy.
Clinical Proof of Concept for LSD Gene therapy
In 2013, Biffi et al. were the first to publish clear clinical proof-of-concept data for a gene therapy in an LSD with CNS involvement . Investigators used a lentiviral vector for ex-vivo transduction of stem cells from three patients diagnosed with late infantile metachromatic leukodystrophy (LI-MLD).
MLD is a caused by mutations in the ARSA gene resulting in buildup of sulfatide in CNS cells, leading to demyelination and neurodegeneration. Late infantile MLD patients present symptoms by their third birthday and usually die within a few years of symptom onset. There are no treatments that substantially delay the progression of MLD.
In this trial, investigators used a “control group” that consisted of disease progression data from older siblings of the enrollees, who also were diagnosed with LI-MLD. Patients demonstrated above-normal expression of ARSA throughout the hematopoietic cell lineages at one year post-treatment. Importantly, at 18-24 month follow-up all three treated patients had their disease progression halted and/or slowed compared to “controls” and a natural history cohort of untreated LI-MLD patients.
Despite the immense read-through for the potential of ex-vivo lentiviral gene therapies in other LSDs with CNS involvement, the use of this treatment modality may be limited – the transgene is only expressed in the CNS by cells with hematopoietic lineage, such as microglia. Gene therapy for LSDs rely on individual cells expressing adequate amounts of missing protein to prevent storage buildup. In order to maximize efficacy, transgene expression should be widespread to all cells in the CNS – not just those with hematopoietic lineage. This is why much of the excitement for LSD gene therapy (and CNS gene therapy as a whole) has risen from the use of AAV vectors which have the ability to lead to widespread transduction in the CNS.
In 2014, Tardieu et al. were the first group to publish clear clinical proof-of-concept data for in-vivo gene therapy of a LSD with CNS involvement . The investigators enrolled four patients diagnosed with Mucopolysaccharidosis Type IIIA (MPSIIIA, Sanfilippo A) and treated these patients with an AAVrh.10 vector carrying the SGSH and SUMF genes. As a reminder, Sanfilippo A is caused by a mutation in the SGSH gene resulting in the typical pathophysiology seen in LSDs with CNS involvement. The investigators delivered a total dose of 7.2E11 vector genomes (vg) per patient at 12 deposits in the brain (via 6 image-guided tracks). Based on neurological and clinical evaluations, three treated patients were considered clinically stable, with the fourth showing improvement, at 52 weeks post-treatment. This contrasts the disease’s natural history.
Lysogene obtained an exclusive license to develop AAVrh.10-SGSH-SUMF in 2013, and renamed the asset SAF-301. Lysogene is currently conducting a 5-year follow-up study of the original four patients treated with SAF-301 .
LSD Company Landscape
Table updated 7/6/15 with new information concerning REGENXBIO's LSD programs
Looking into the Future
With the recent improvement in AAV vector manufacturing and delivery, I’m optimistic that within the next several years future gene therapy trials designed to treat the CNS disease involvement in LSDs could show modest clinical efficacy. These future positive clinical trial data could position gene therapy as a treatment option (not a cure) to add to the treatment arsenal for LSDs.
Further down the road, novel AAV vectors (via rational design and directed evolution) with improved transgene cassettes are going to be moving into the clinic. These novel AAV vector/transgene cassettes are the future of in-vivo CNS gene therapy – as well as in-vivo AAV gene therapy as a whole.
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