Article from Nature Medicine
When Alexis de Tocqueville warned of the “tyranny of the majority,” he was not thinking about neuroscience. But one could argue that in recent years, a groupthink has emerged in which many companies and academic labs decided to chase the same targets in certain neurological diseases. With Alzheimer’s disease, for example, the search for treatments has focused on clearing amyloid-beta (Aβ) protein from the brain, and in Parkinson’s research, scientists similarly homed in on alpha-synuclein (α-synuclein). But recent cash infusions into start-ups that are pursuing different potential villains in these diseases and in other similar disorders suggest that the scientific hegemony in neurodegeneration is starting to give way to a diversity of approaches.
The widening of focus to new targets comes amidst an ever-growing need for treatments for age-related neurodegenerative disorders. In 2014, the most recent year for which data is available from the US Census Bureau, there were more than 46 million people aged 65 or older living in the US—and that number is estimated to double by 2060.
Scientists have known for years that the brains of people diagnosed with Alzheimer’s disease contain high amounts of Aβ plaques, a finding that suggests that these plaques perhaps contribute to the condition. Many therapeutic strategies have therefore focused on the removal of Aβ plaques, in the hope that doing so could stop or slow disease progression. Cambridge, Massachusetts-based Biogen’s drug aducanumab is such an Aβ eliminator. Currently in two large phase 3 trials, aducanumab is a monoclonal antibody that works by binding to two specific forms of Aβ—fibrils and oligomers—and that, through a phagocytic mechanism, clears aggregates of the protein. Including these two trials and another two from Biogen on other Aβ-related products, there are currently at least seven clinical trials in phase 2 or later to test Aβ-based therapies.
When it comes to Parkinson’s disease, many efforts in recent years have centered on α-synuclein, a protein that is thought to help regulate neurotransmitter function. α-synuclein is a major component of Lewy bodies—protein aggregates that are a telltale sign of Parkinson’s disease. In August 2015, two different drugs entered clinical trials, each of which relies on an approach to target α-synuclein and thus reduce its presence and toxicity in the brain. Another study, conducted by Prothena Biosciences in collaboration with Hoffman-LaRoche, was initiated in early 2014, but despite reporting positive results in June 2015 from a dose- escalating study, it is still in phase 1 testing.
In spite of the excitement surrounding the α-synuclein and Aβ strategies, however, no therapy is yet at hand. Available drugs for Alzheimer’s disease do not treat the underlying causes of the illness but rather its symptoms, such as stress, memory loss and disorientation. Now, to supplement and perhaps expedite the search for more effective treatments, start-ups are increasingly investing in new approaches aimed at finding therapies for neurodegenerative diseases. More than a handful of such companies have ramped up their efforts in recent months, each raising several million dollars in funding.
Lysosomes in the limelight
In recent years, evidence has emerged that lysosomal dysfunction inside neurons might contribute to Parkinson’s disease. Lysosomes are organelles that are responsible for breaking down and digesting unwanted molecules and microorganisms from the cytoplasm. When their function is disrupted because of mutations in the genes that encode enzymes used by lysosomes to function, waste accumulates in the lysosomes of nerve cells, which results in nerve damage and death as a result of toxicity. Groups such as Ashkenazi Jews are considered to be at high risk of developing lysosomal disorders because many of them carry at least one copy of the mutation that causes a lysosomal-storage disorder called Gaucher disease; they are also at higher risk of developing Parkinson’s disease than are those who are not carriers (JAMA Neurol. 71, 752– 757, 2014). People diagnosed with Gaucher disease are also likely to develop Parkinson’s, on average, about ten years earlier than are their counterparts without the disease.
Enter Cambridge-based Lysosomal Therapeutics, a company founded in 2013 that is focused on manipulating lysosomal function to treat neurodegenerative disorders. “Cells don’t regenerate in the brain in the same way that stomach or skin cells do,” says Kees Been, CEO of the company. “Over time, as nerve cells get depleted, at some stage you see the effect.”
Lysosomal Therapeutics is developing a small molecule that activates the enzyme glucocerebrosidase (GCase). Mutations in the
12 gene that encodes GCase cause a buildup of glucocerebroside in the lysosomes of cells, which leads to Gaucher disease. In those who carry the GCase mutation, “the enzyme activity level is at a 60–70% level range, and that’s a risk factor for Parkinson’s disease,” Been explains. As a result, the entire pathway is compromised. Been likens the situation to a blockage in a river. “Getting rid of the blockage”—in this case, activating the GCase enzyme—“restores the flow in the river and, as a result, lysosomal health.”
Since it was founded, the company has raised $4.8 million in seed funding and, in January of last year, it received an additional $20 million in series-A funding. It was also the recipient of a $230,000 grant from the Michael J. Fox Foundation. Lysosomal Therapeutics is about to wrap up the lead-optimization phase of development, and it will start preclinical testing of its GCase small-molecule drug. The company hopes to file an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) by mid-2017.
Delving into degenogenes
Another Cambridge start-up that is taking a different tack to treating neurodegenerative disorders is Yumanity Therapeutics. The company was founded a little more than a year ago and has a large focus on Alzheimer’s disease. “We are interested in therapies targeting Aβ toxicity, but not in the traditional way,” says Ken Rhodes, who was formerly at Biogen but is now serving as Yumanity’s chief scientific officer. “At Biogen, we focused on Aβ removal as a way to treat toxicity, but Humanity is focused on downstream toxicities mediated by Aβ, such as protein misfolding.” Rhodes adds that the company is also interested in other approaches to treating Alzheimer’s disease. These include work on apolipoprotein E4 (ApoE4), an allelic variant of the APOE gene that is considered a risk factor in the development of Alzheimer’s disease, and trying to understand ApoE4’s effect on Aβ.
Yumanity is using yeast that has been engineered to express ApoE4 or Aβ. Many of the cellular pathways that are damaged by Aβ, such as protein folding, are highly conserved in yeast cells, and yeast has the advantage of revealing these pathways relatively quickly compared to other model organisms. Specifically, the company is looking for genes, proteins and drug- like small molecules that modify Aβ toxicity. “We use medicinal chemistry to optimize these drug-like small molecules into candidates that are suitable for clinical development,” Rhodes says. “The speed at which we can move in the yeast platform is extraordinary.” In a second step to this screening, Yumanity uses patient- derived induced pluripotent stem cells (iPSCs)
to validate the candidates that are identified using the yeast-based platform. The company, which has not disclosed any of its earnings, has identified four different targets so far using these platforms, and it is in the lead-optimization phase.
Across the country in South San Francisco, California, former Genentech employees Ryan Watts, Alexander Schuth and Marc Tessier-Lavigne launched Denali Therapeutics in May 2015. The new venture aims to discover and develop therapies for a range of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The company disclosed that in its initial round of funding, with investments from four venture- capital firms and various private sources, it raised $217 million.
Denali’s science hinges on what Watts calls “degenogenes,” which are genes that, when mutated, cause neurodegeneration. Although Watts declined to name the specific targets that the company plans to pursue, he said that its four discovery programs are aimed at finding small- molecule and antibody-based therapeutics. Two of the four programs look at pathways that trigger disease; one of these includes exploring degenogenes to discover how they cause degeneration, whereas the other will explore the role of endolysosomes—hybrid organelles that are formed through the fusion of endosomes and that transport cellular material to lysosomes to be digested. The other two discovery programs aim to look at effector or accelerator pathways—pathways that, when modified, further exacerbate disease. In this context, Denali will focus on the degeneration of axons and synapses, in addition to examining the pathology and genetics behind inflammation in the brain, particularly in microglia. “I absolutely feel like we need to target additional pathways that may or may not feed into the Aβ pathway,” Watts says.
For Denali, the key to success is finding the right patient populations in which to test novel therapies. “When is the right time to intervene?” says Watts, the company’s CEO. “Many of the studies that have been done didn’t pre-select patients for amyloid load.” So for their trials, Denali plans not only to sequence the genome of all patients to test for genetic risk factors such as the presence of ApoE4, but also, through imaging, to ensure the presence of Aβ.
A nod to neuroinflammation
In the last 18 months, Annexon, also in South San Francisco, has raised $34 million in funding to develop its products, which include a monoclonal antibody designed to treat diseases such as Alzheimer’s, according to CEO Doug Love. Called ANX005, the monoclonal antibody binds to and inhibits C1q, which is part of the classical complement pathway that activates antibody-driven immune responses. C1q may also be responsible for the removal of excess synapses that arise during early brain development, according to Love.
This C1q-mediated clearance of synapses may also help to explain the synaptic loss observed in Alzheimer’s disease. Stressors caused by the disease seem to trigger dormant C1q, which then activates the classical complement pathway (Cell 131,1164–78, 2007). ANX005 is designed to clear C1q so that when age-related stressors such as inflammation are present, there is little or no C1q to trigger. In blood and in cerebrospinal fluid, ANX005 knocks down C1q to undetectable levels. In addition, “We know our antibody gets past the blood-brain barrier,” Love says.
This approach targets the underlying problem of synaptic loss, which is common to many neurodegenerative conditions. And because C1q levels can be measured in blood, the treatment could be optimized for those individuals who are most likely to need anti-C1q therapy. ANX005 is currently in the preclinical phase, and the company is pursuing INDs for indications such as Alzheimer’s and Huntington’s disease. The product is also being studied as a potential treatment for frontotemporal dementia, spinal muscular atrophy and post-stroke epilepsy. However, because C1q has a role in mediating host defense against infection, the clearance of C1q does open up the risk of immunodeficiency. Love hopes that adjusting the dosing of the product, however, may offer a way to circumvent the problem.
Bigger companies are delving beyond conventional targets as well. For example, despite having three Aβ-related products in the pipeline—aducanumab, another monoclonal antibody known as BAN2401 that binds to Aβ protofibrils, and E2609, an inhibitor of β-secretase enzyme, which helps to produce Aβ—Biogen is still pursuing non-Aβ–based therapies. “We believe that multiple therapies are likely needed to overcome these diseases,” says Samantha Budd-Haeberlein, Biogen’s vice- president of Alzheimer’s Disease, Neurology Discovery & Development. She adds that other approaches, targeting components involved in neuroimmunology or even protein trafficking, are also worth a look. The company is currently collaborating with Proteostasis Therapeutics in Cambridge, Massachusetts, to study the ubiquitin-specific protease 14 (USP14) enzyme, which, when activated, enables proteasomes in cells to destroy proteins. The hope is that activating USP14 will help to clear the protein aggregates that are hallmarks of both Alzheimer’s and Parkinson’s disease.
There are still others pursuing novel strategies against neurodegenerative disorders, such as San Francisco–based Alector, which raised $32 million in series-C funding in September 2015. Since it was founded in October 2013, the company has focused on doing what immunotherapy has done for cancer, according to Arnon Rosenthal, CEO of Alector and chairman of Annexon’s board of directors. “All the rage now, instead of targeting the cancer cell, is to target immune cells,” Rosenthal says. “If you look at the risk genes for Alzheimer’s disease, more than half of them are only expressed in the immune system but not in the nervous system, so it’s clear that the immune system plays a role.”
In the setting of neurodegenerative disease, immune cells such as microglia become toxic and inflammatory, which worsens the disease condition. Alector hopes to create a monoclonal antibody that will target different receptors to restore the function of microglia.
“We are developing antibodies that will modulate immune genes expressed on immune cells,” Rosenthal says. And although he declined to disclose them, he said that the company is focused on a set of 12 such targets. If the immune system is better functioning, it’ll be better able to target things such as Aβ, Rosenthal explains. “We’re generating a better police force and letting it decide how best to deal with [the perpetrators].” The company, whose targets are still in pre-clinical testing, plans to file INDs within the next 18 months.
Lysosomal Therapeutics’ chief scientific officer, Peter Lansbury, says that smaller companies face steep competition when chasing well-known targets such as Aβ. “It’s an area that’s saturated, and there’s not an opportunity for start-up–like people, because big companies like [Eli] Lilly and Biogen have made big investments,” he says. However, he likens the direction of neurodegeneration drug development to that of cancer therapy: “We’ll be treating Alzheimer’s disease and Parkinson’s disease more like we’re treating cancer,” Lansbury says. “We won’t be classifying based on symptoms, but based on underlying defects.” For this reason, newer ventures chasing different targets may do well in finding viable approaches against neurodegeneration, he adds.
“Although Aβ-based approaches aren’t going away,” Love says, “you are seeing an advent of other approaches.”
Shraddha Chakradhar is Nature Medicine’s assistant news editor, based in Cambridge, Massachusetts.