Gene therapy is making a comeback in the world of neurodegeneration research, as evidenced by this year’s Society for Neuroscience conference held in Chicago. With the success of Novartis Zolgensma (gene therapy for spinal muscular atrophy in infants), money and ideas are circulating like never before. Hence a rapidly expanding clinical research pipeline for gene therapy-based treatments for neurodegenerative disease.
There was a time when researchers were bullish on gene therapy research for neurodegenerative disease. Two decades ago, for example, researchers engineered fibroblasts (derived from the skin of Alzheimer’s patients) to produce nerve-growth factor, sliding them into each study participant’s basal forebrain reports Tom Fagan from AlzForum. It was hoped that that neurotrophin could impede the memory-robbing neurodegeneration—it did not, and the research for all practical purposes lie dormant.
The New Stance
Mr. Fagan reports, “What was once considered risky, expensive and unlikely to succeed is now seen by many as risky, expensive—and quite likely to succeed.” What a difference a couple of decades makes, and some progress in other fields makes!
Now researchers are increasingly focusing on disorders triggered by single-gene mutations. They believe that gene-based therapies represent, perhaps, the most probable opportunity to slow down or even prevent neurodegeneration.
Society for Neuroscience Conference
At the Chicago event, participants had no breaking news, but there was a clear sense that the momentum for gene therapy-based research was gaining speed. Moderators such as Jeff Kordower (Rush University) introduced the scope and challenges of this research while Asa Abeliovich (Columbia University) moderated a translational roundtable—she recently co-founded Prevail Therapeutics in New York as well.
Zolgensma Triggers Momentum
Humans and history tend to go in waves—from micro-fads to macro trends; research is not immune to this exceptionally human dynamic. Hence with the FDA approval of Zolgensma (the world’s most expensive dug at $2 million per treatment) has helped catalyze tremendous interest back into gene therapies in multiple fields, including central nervous system-based disciplines. Known as AVXS-101, the gene therapy was developed at Nationwide Children’s Hospital, Columbus, Ohio. Their researchers utilized an adeno-associated virus (AAV) to deliver billions of replicas of the survivor motor neuron one gene to the brain reported Mr. Fagan from AlzForum. After a successful pilot and Phase I study (significant improvements to the 15 treated infants), scientists were intensely moved to watch a video of a little girl treated with AVXS-101 walking down some stairs.
A Game Changer
Now those scientists with a mission to treat neurodegenerative disorders are riding the momentum of AVX-101 wave. And why not? Clive Svendsen, Cedars-Sinai Regenerative Medicine Institute, Los Angeles, declared, “It is really the tremendous success with SMA that has renewed interest in gene therapy.” And Bart De Strooper, Dementia Research Institute, London, spoke with AlzForum and noted: “The success in SMA patients of both gene therapy and antisense therapy has revived interest in the whole area.”
AlzForum’s Fagan noted today researchers seem to combine gene therapy and antisense therapy under the gene-based treatment, and in fact, Fagan reminds the reader that nusinersen, an SMA antisense therapy, works in babies with SMA Type 1 and is FDA approved. However, with antisense therapy, the treatment must be delivered indefinitely while with gene therapy, it may potentially be administered just once.
Gene Therapy as Applied to Neurodegenerative Disease?
At the conference, researcher scientists discussed different strategies for treating adults combatting Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease (HD) and Parkinson’s disease (PD) to name a few. A new momentum is building, from preclinical animal lab research to actual clinical trials. Some treatments focus on are designed to stop the loss of a function while others are designed to rescue dying neurons. AlzForum noted that some scientists are targeting rare childhood diseases of lysosomal storage as that may offer an opening to treat atypical phenotype in age-related neurodegeneration.
AlzForum offered the reader some exciting research and study updates, including:
- ApoE gene therapy trial, a Phase I trial, started enrolling patients. Ronald Crystal leads the study from Weill Cornell Medical College, New York. In this study, the investigators will inject adeno-associated virus transporting the gene for ApoE2 into patients with early to late-stage AD who happened to have inherited two copies of ApoE4 reports Fagan. In an attempt to counteract the effects of the risk allele, the investigator floods the brains with a protective allele of this apolipoprotein. The study’s procedure involves the recruitment of 15 participants with biomarker-confirmed AD.
- A similar ApoE2 gene therapy currently is in preclinical development (e.g., animal research) and is led by Beverly Davidson, Children’s Hospital of Philadelphia.
- Asa Abeliovich (Columbia University) discussed Prevail Therapeutics’ programs for forms of Parkinson’s Disease (PD) for frontotemporal dementias that are believed to be caused by risk alleles. A clinical trial has commenced for glucocerebrosidase-based gene therapy. GCase, an enzyme, is essential for functioning lysosomes. So if there is a loss-of-function mutation in both copies of the GBA1 gene, apparently patients can develop Gaucher’s, a lysosomal storage disease. While the most severe forms can start in babies (most die before age 2), milder cases can trigger later-onset Gaucher’s; and heterozygous mutations in GBA1 boost the risk for Parkinson’s Disease. This indicates that the restoration of GCase a distinct strategy for Parkinson’s Disease. Abeliovich and peers constructed AAV-9 vectors to deliver normal GBA1 into the brain to restore the GCase production report AlzForum.
And in fact, Abeliovich reported that in preclinical studies, their AAV9-GBA1 construct called “PR001” rescued both lysosomal and brain function in models of GCase and deficiency and of PD. Follow the link to the source or Abeliovich’s website for more information.
- AAV-GAD, gene therapy for PD evidenced promise in Phase 2 clinical trial. This asset was acquired by MeiraGTx, New York, which plans to continue to develop gene-based treatment in the U.S. and Europe, according to founder Samuel Waksal.
- Passage Bio, Philadelphia, is targeting the commencement of clinical trials next year with its AAV-GRN vector.
- MeiraGTx, New York, again having recently acquired an AAV-GAD gene therapy asset, is taking a different approach than Passage Bio. AlzForum reports that they developed an AAV carrying UPF1, which encodes regulator of nonsense transcripts 1. This protein supports the clearing out of aberrant RNAs via the nonsense-mediated decay. The sponsor targets that this will restore homeostasis to RNA processing. AAV-UPF1 will enter clinical trials for FTD and all ALS forms except for those caused by mutations in SOD1.
Novartis (Basel) and REGENXBIO (Maryland) are involved with SOD for ALS and are developing a vector in preclinical testing.
- Cedars-Sinai (Svendsen) focuses their lab on tacking ALS with ex vivo gene therapy. They seek to engineer clinical-grade human stem cells to generate glial-derived growth factors and, after that, inject and administer into the spinal cord. Investigator Svendsen hopes the cells will churn out enough of the neurotrophin to afford protection to spinal cord motor neurons. They are testing in Phase I/II clinical trial involving 18 ALS patients. They have received these cells into one side of their spinal cords—this establishes a situation where each patient serves as his or her control. How will they know if this works? The patient would regain mobility on the injected side. This clinical trial recently concluded in October 2019, and Svendsen expects the results to be available in a few months.
Now with a follow-up study, this team is attempting a comparable study with induced pluripotent stem cells, allowing them to transplant autologous cells into patients and hence avoiding immune rejection.
Call to Action: AlzForum is a fantastic resource for those interested in following preclinical and clinical trials involving neurodegenerative disease. We recommend those interested follow the site. TrialSite News takes a keen interest in this topic and seeks the support of this class of research.