In this edition of RMNU🔬, we’re keeping up with multiple research advances in the vision repair field. Also, Vertex Pharmaceuticals is dropping a big therapeutic from their portfolio, and Longeveron has a new publication.
Of course, yet another round of updates on Parkinson’s cell therapy awaits you.
Let’s jump in!
Pick of the Season
Source: Pexels – Jonathan Borba
Optogenetics for vision loss
Optogenetics was the beating heart of my thesis. Explaining it to someone for the first time is a chance I will always jump at. When this story crossed my desk, it flew to the top of my working document for reasons that will become obvious as you read on.
Optogenetics can be many things to many people. To the neuroscientist, it is a vital part of the brain mapping and decoding toolkit. To the cell biologist, it is a tool enabling the manipulation of specific macromolecular interactions. Most relevant to this story, vision scientists are exploring it as a logical solution to vision loss. But how does it work?
I wrote an in-depth piece for Signals back in 2019 all about optogenetics. The quick version is that we can engineer cells so that they physiologically respond to particular wavelengths of light. The nature of this response varies depending on the field. In forms most relevant to the present highlight, we take opsin genes encoding light-sensitive ion channels or pumps derived from microorganisms (or even insects), and deliver them via AAV to the cells we want to study, in vitro or in vivo. In the case of neurons, for instance, activation of these opsins replicates the electrochemical phenomenon that produces an action potential or electrical impulse – arguably the basic unit of brain communication at the cellular level… and yes, that’s as powerful as it sounds.
In Mohanty et al.’s Phase I/IIa trial, the authors decided to tackle inherited retinal degenerations, including retinitis pigmentosa, wherein light-sensitive photoreceptor cells in the eye, such as rods and cones, are gradually lost. To improve vision, they engineered a synthetic opsin (MCO-010) capable of responding to multiple wavelengths of light – a big change to the usual monochromatic character of optogenetic tools – to enhance light responsiveness and simplify their overall approach.
From there, they genetically targeted bipolar neurons for delivery, which act as the relay between photoreceptors and ganglion cells (that are responsible for transmitting visuals from the eye to the brain). This makes sense, as it enables the next layer of cells to sense the light themselves in absence of the layer lost to disease. This approach allowed them to restore some features of functional vision to legally blind individuals; videos accompanying the publication demonstrate the results live, including the before and after.
Of course this was a very small trial, but seeing people walk towards a light they couldn’t detect before was quite compelling and represents a significant shift in quality of life for these individuals. A few treatable opacities were noted—possibly naturally occurring or AAV-related—but no serious adverse events were reported, and the treatment was well tolerated. There was also no severe inflammation indicating an immune response to the nonhuman proteins; this makes sense, as the eye is immune privileged. This privilege is sometimes compromised during disease, which is why it’s still worthy of mention.
Now you might be thinking, well this isn’t the first attempt at vision restoration in humans using optogenetics. If so, you’d be correct. A similar attempt was made back in 2021, but it involved the ChrimsonR opsin along with special goggles that were necessary for any functional improvement to manifest. These goggles modulated the light intensity and wavelength to match ChrimsonR’s peak activation. That work by Sahel et al. represented a celebrated first proof-of-concept in this field, though much work remained. Broadening opsin sensitivity, as Mohanty et al. did, reduced the need for external light-converting devices and better accommodated natural lighting conditions. There’s still plenty of work ahead, but cautious optimism is certainly justified.
Some other vision-related research to comment on:
- Cultivated autologous limbal epithelial cell (CALEC) transplantation for limbal stem cell deficiency: a phase I/II clinical trial of the first xenobiotic-free, serum-free, antibiotic-free manufacturing protocol developed in the US. While this paper is exciting, I just wanted to highlight that using healthy limbal stem cells from one eye to heal a damaged cornea in the other is not new, and the authors don’t claim it to be so; in fact, we’ve been doing it here in Canada for a while. However, that’s been left out of a lot of the top coverage on this story, to my surprise. Some people reading these headlines will think this team invented the treatment, which isn’t the case. The actual novelty offered by this protocol is that manufacturing guidelines in the U.S. are different, preventing autologous limbal stem cell transplants in their current form from being used by our Southern neighbours… until now, potentially. The researchers behind this paper modified various in vitro steps to adhere to the FDA’s Good Manufacturing Practices, meaning this treatment might soon be accessible to patients in the U.S. – a great accomplishment.
- Plus, another limbal stem cell deficiency-related paper: A novel therapy to ameliorate nitrogen mustard-induced limbal stem cell deficiency using lipoprotein-like nanoparticles.
- Identification and characterization of human retinal stem cells capable of retinal regeneration. Some context: Derek van der Kooy’s lab, where I completed my thesis work, discovered retinal stem cells (RSCs) in mice (2000) and in humans (2004). They transplanted these human RSCs into both mice and chicks, demonstrating they could integrate in vivo. The van der Kooy lab continued to work with RSCs over the years alongside frequent collaborator Dr. Molly Shoichet, plus other international colleagues (2010). They published evidence suggesting that these cells can differentiate into mature retinal cell types (2012), including photoreceptors, and selectively differentiated them to either rods or cones (2018). To explore therapeutic avenues, they 1) developed hydrogels to deliver the cells to animal models of retinal degeneration in vivo (2020), thereby improving vision; and 2) activated proliferation in vivo by modulating niche factors (2021), including R&D on a small molecule to this end with Endogena Therapeutics. It seems that Science’s news coverage of the new publication by Liu et al. missed this context; unfortunately, they report that the original RSC work by the van der Kooy lab was “discounted” in 2009, citing a paper that employed a protocol deviating from the original. Thus, their research group could not replicate the results. Something as simple as the choice of glass or plastic to culture cells can affect the end product, and that appears to be what happened. Either way, “discounted” is probably not an accurate characterization of work that has since continued into the validation stages of the research pipeline. There has been debate and discussion on the matter, but healthy skepticism in science is natural. Either way, it will be interesting to compare the RNA sequencing data from this new publication to the van der Kooy lab’s mouse RSC RNA sequencing dataset.
Vertex Pharmaceuticals drops encapsulated T1D cell therapy from portfolio
In the summer 2024 edition of RMNU🔬, I included a few updates about Vertex Pharmaceuticals’ allogeneic stem cell-derived pancreatic islet cell therapy, VX-880 (which is now being called Zimislecel). At the time, I mentioned that clinical results in patients with type I diabetes (T1D) were thus far positive, and that the company was also working on a newer, device-encapsulated version of the product that wouldn’t require immunosuppressants: VX-264. Given how well VX-880 had been doing in its trial, there was much cautious optimism around VX-264. Things can change very quickly in the human phase, and that brings me to Vertex’s latest announcement: While VX-264 was deemed safe, efficacy couldn’t be proven in their Phase I/II study. It seems like the device protecting the cells from the patient’s immune system was preventing the therapeutic effects, so now the team is working towards understanding what exactly went wrong. Just like that, the field is wide open and it’s anybody’s race again.
VX-880 still appears to be going strong, so much so that their Phase I/II trial was upgraded to Phase I/II/III. Enrolment and dosing for approximately 50 patients are slated to wrap in the first half of 2025.
Longeveron update: Phase IIa results for Alzheimer’s therapy published
I mentioned in the May 2024 edition of RMNU🔬 that Longeveron had wrapped its Phase IIa CLEAR MIND trial with positive results, testing an allogeneic mesenchymal stem cell (MSC) therapy for mild Alzheimer’s disease (AD). You can now read about the findings in detail, as they’ve just published their results in Nature Medicine.
As a refresher, the intravenous treatment, called laromestrocel or Lomecel-B, is a bone marrow-derived allogeneic mesenchymal stem cell therapy. The goal is to slow the clinical progression of AD, including brain atrophy and neuroinflammation. Immunosuppression isn’t required, as the cells are relatively immunoprivileged; this is partly because of low-to-undetectable expression of molecules that would usually trigger the immune system by presenting as “foreign” – major histocompatibility complex (MHC)-II and MHC-I expression – plus immunomodulatory effects.
Based on 48 patients, 36 of whom received the treatment with the rest having received a placebo, positive outcomes included better test scores measuring quality of life, cognitive ability and functional capacity – plus a slower volumetric decline of the brain, and reduced neuroinflammation. A Phase II/III trial is currently in the works.
Longer follow-up times are something the authors acknowledge as necessary in the future, since their Phase IIa was 39 weeks.
Given that this is a pretty general MSC therapy that’s reaching not just the brain, but also other parts of the body, it will be interesting to hear about what other benefits these trial participants might experience at the individual level, especially since MSCs are being tested across a wide array of disease indications right now. In fact, Longeveron is testing the same treatment for, more generally, aging-related frailty.
I also came across an interesting quote given to CGTLive by Dr. Joshua Hare, the founder and chief science officer of Longeveron:
“Other classes of drugs produce a condition called Alzheimer’s related imaging abnormality (ARIA). It was first detected on MRI and it corresponds to either brain edema or hemorrhage in the brain, and it can be clinically significant. […] with Lomecel-B, there’s no evidence of ARIA. […] One of the key things that we did in the study, just to emphasize, is repeat dosing. Recurrent dosing with Lomecel-B is just as safe as a single administration.”
These two elements struck me as worthy of keeping in mind, especially as we evaluate other therapeutic candidates that come forward.
Update and summary: Parkinson’s cell therapies
April gave us two new publications on stem cell-derived dopamine neuron replacement therapies for Parkinson’s Disease (PD); one comes to us from Yamanaka’s CiRA, and the other is from BlueRock Therapeutics. The latter has published 18-month data from its Phase I trial in Nature, and confirms that its Phase III is slated to kick off before mid-2025 (see below for links).
I’ve put together a table to summarize treatment approaches and trial phases across some of the most prominent teams. It’s not exhaustive (there are over 55 cell therapies for PD in R&D right now), but it could help you keep track of the institutions/companies that are most frequently discussed in this context.
| Team | Therapy and/or Trial name | Cell type | Trial phase | Outcome |
| Aspen Neuroscience | ANPD001 – ASPIRO | Autologous iPSC-derived dopaminergic progenitors | Phase I/IIa (Ongoing) | Press release: Cohorts 1 & 2 dosed; well tolerated far. |
| BlueRock Therapeutics (Bayer) | Bemdaneprocel – exPDite | hESC-derived dopaminergic progenitors | Completed Phase I; Phase III planned for H1 2025. | Tabar et al.: Well tolerated; signs of engraftment.
|
| CiRA, Kyoto University | Kyoto Trial | Allogeneic iPSC-derived dopaminergic progenitors | Phase I/II | Sawamoto et al.: No serious adverse events; PET evidence of cell survival. |
| Lund & Cambridge University Teams | STEM-PD Trial | hESC-derived dopamine progenitor cells | Phase I/IIa | Well tolerated so far.* |
*I’ve come across a death in the STEM-PD trial. The patient seems to have succumbed to an infection that crept in amidst the immunosuppression required for treatment, rather than the surgical procedure and/or stem cell product themselves. An unfortunate example of why autologous iPSC-based therapies are being pursued so aggressively.
On that note, I do have a couple of honourable mentions. Both are Harvard-affiliated in Boston, and both are using autologous iPSCs:
- Treating Parkinson’s Disease Through Transplantation of Autologous Stem Cell-Derived Dopaminergic Neurons. (Massachusetts General Hospital)
- Autologous iPSC-Derived Dopamine Neuron Transplantation for Parkinson’s Disease. (Brigham & Women’s Hospital)
Most of these trials are also hinting at efficacy, but it’s too early to say for sure. Results are definitely promising in these early phases. Improved safety aside, I’ve already commented on the theoretical drawbacks of autologous iPSC therapies for diseases with genetic components in a previous post, but hopefully there’s lasting benefit in practice. If not, future treatments might benefit from some degree of in vitro genetic interventions prior to transplantation. We’ll see in time!
Additional recommendations
Beauty clinics in UK offering banned treatments derived from human cells. I’ve written a separate article about exosomes and the way they’re regulated globally, keep an eye out for this.
A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models. Really interesting work. I will note, however, that I think we need a new name for the “suicide gene” system. It’s an important tool, so we’ll probably be seeing more of it. While it might be a simple and accurate descriptor, suicide is a charged word for a lot of people.
Japan’s big bet on stem-cell therapies might soon pay off with medical breakthroughs. So much impactful regenerative medicine work is coming from Japan across subfields. I’ve written about at least three big Japanese research headlines this year alone – stem cells for vision loss, Parkinson’s (above), and also tooth regeneration (though the latter isn’t a stem cell therapy, it’s an antibody-based drug).
Sarepta Says Teen Died After Its Gene Therapy Treatment. and Independent DMC Concludes that Risk-Benefit Ratio for Sarepta’s DMD Gene Therapy Elevidys Remains Favorable. It’s always troubling when a patient dies during a clinical trial. In this case, it appears to have been caused by a combination of the AAV used for gene delivery, in addition to a cytomegalovirus infection, both of which can be quite hard on the liver. Lots of people may benefit from these therapies, but it’s always important to be reminded of the risks, as well.
Don’t rush promising stem-cell therapies.
Human assembloid model of the ascending neural sensory pathway.
A call to action for deciphering genetic variants in human pluripotent stem cells for cell therapy.
Paralysed man stands again after receiving ‘reprogrammed’ stem cells.
Age-related blood condition counteracted with a common diabetes drug.
Google’s Gemini AI schools Google Search on its risky stem cell results.
Proliferation history and transcription factor levels drive direct conversion to motor neurons.
The Business of Promoting Longevity and Healthspan.
They Wanted a Quick Fix for Hair Loss. Instead, These Young Men Got Sick.
Stem cell injections for osteoarthritis of the knee.
Immune-mediated regeneration of cell-free vascular grafts in an ovine model.
RFK Jr.’s regenerative medicine roundtable on stem cell deregulation raises red flags.
Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity.
Optimizing stem cell infusion timing in the prevention of acute graft-versus-host disease.
Fibroblast-derived osteoglycin promotes epithelial cell repair.
Orca-T outperforms standard stem cell transplant for blood cell cancer.
F.D.A. Approved Lab-Grown Blood Vessel Despite Warnings.
Fabrication of a novel 3D-printed perfusion bioreactor for complex cell culture models.
MCL‑1 safeguards activated hair follicle stem cells to enable adult hair regeneration.
Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis.
FDA RMATS and other status changes
Adia Labs Secures FDA Registration for Adia Vita, Expands Regenerative Medicine Nationwide.
Nature Cell wins FDA breakthrough designation of Jointstem.
Allogene Therapeutics’ ALLO-329 Snags FDA Fast Track Designations for 3 Rheumatology Indications.
Lyla El-Fayomi
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