Cyanocobalamin

Pictured: Illustration of a motor neuron being degraded/iStock, Dr_Microbe Given current limitations in existing therapies, the biopharma industry is adopting innovative approaches to amyotrophic lateral sclerosis, seeking to develop more effective disease-modifying drugs, according to a new report from data and analytics firm GlobalData. Currently, there are more than 100 investigational pipeline candidates being studied for amyotrophic lateral sclerosis (ALS) in all stages of development and across various major markets, including the U.S., Canada, Japan and the U.K. The candidates leverage different innovative modes of action against ALS, according to GlobalData. Some block the leukotriene receptor, while others make use of stem cells. Other investigational therapies include tyrosine kinase inhibitors, monoclonal antibodies, vitamin B12 and IL-2 antagonists. ‘‘To address the lack of efficacious options, the treatment horizon is now abuzz with exploration of novel approaches,” GlobalData healthcare analyst Momna Ali said in a statement, adding that among these investigational therapies is “a promising dozen” currently in Phase II and III studies. Ali expects some of these ALS candidates to secure regulatory approval and hit the market within the next five years. “This not only offers pharmaceutical companies’ lucrative opportunities for profit but also presents a ray of hope for patients eagerly waiting for disease-modifying drugs,” Ali said. ALS has long been an attractive target for biopharma companies. The disease is characterized by progressive loss of muscle control, which manifests as trouble walking, weakness in the limbs, slurred speech and cognitive and behavioral changes. In April 2023, the FDA approved Biogen and Ionis’ antisense oligonucleotide Qalsody (tofersen) for the treatment of superoxide dismutase 1 (SOD1) ALS. Up to 20% of familial cases of ALS and up to 2% of all cases are linked to underlying SOD1 genetic mutations. Qalsody is the first therapy approved to address a genetic form of ALS. Other approved treatments include Amylyx’s Relyvrio (sodium phenylbutyrate and taurursodiol), Sanofi’s Rilutek (riluzole) and Mitsubishi Tanabe’s Radicava (edaravone). Meanwhile, other biopharma companies continue to struggle advancing their own ALS candidates. Last month, Sanofi and development partner Denali Therapeutics announced that their ALS hopeful SAR443820/DNL788, an investigational RIPK1 blocker, could not significantly improve functional performance in the Phase II HIMALAYA trial. In December 2023, the FDA rejected Clene’s bid for accelerated approval for its ALS candidate CNM-Au8, an oral suspension of catalytically active gold nanocrystals. The regulator said that biomarker data were insufficient to support accelerated approval. Also having trouble with ALS is BrainStorm Cell Therapeutics, which in October 2023 voluntarily withdrew its application for its candidate NurOwn. The company’s decision comes after the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted overwhelmingly against approval, noting that there was currently not enough data to support NurOwn’s efficacy. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

The algae P. antarctica has two forms of the enzyme that makes the amino acid methionine, one needing B12, and one that is slower, but doesn't need it. This means it has the ability to adapt and survive with low B12 availability. The presence of the MetE gene in P. antarctica gives the algae the ability to adapt to lower vitamin B12 availability, giving it a potential advantage to bloom in the early austral spring when bacterial production is low. P. antarctica takes in the CO2 and releases oxygen through photosynthesis. Understanding its ability to grow in environments with low vitamin B12 availability can help climate modelers make more accurate predictions. Vitamin B12 deficiency in people can cause a slew of health problems and even become fatal. Until now, the same deficiencies were thought to impact certain types of algae, as well. A new study examined the algae Phaeocystis antarctica's (P. antarctica) exposure to a matrix of iron and vitamin B12 conditions. Results show that this algae has the ability to survive without B12, something that computer analysis of genome sequences had incorrectly indicated. The alga, native to the Southern Ocean, starts as a single-cell that can transform into millimeter scale colonies. The research published in PNAS, "Flexible B12 ecophysiology of Phaeocystis antarctica due to a fusion B12-independent methionine synthase with widespread homologues," conducted by MIT, WHOI, J.C. Venter Institute, and Scripps Institution of Oceanography (UCSD), found that unlike other keystone polar phytoplankton, P. antarctica can survive with or without vitamin B12. "Vitamin B12 is really important to the algae's metabolism and because it allows them to make a key amino acid more efficiently," said Makoto Saito, one of the study's co-authors and senior scientist at the Woods Hole Oceanographic Institution (WHOI). "When you can't get vitamin B12, life has ways to make those amino acids more slowly, causing them to grow slower as well. In this case, there's two forms of the enzyme that makes the amino acid methionine, one needing B12, and one that is much slower, but doesn't need B12. This means P. antarctica has the ability to adapt and survive with low B12 availability." Researchers came to their conclusion by studying P. antarctica's proteins in a lab culture, and also searching for key proteins in field samples. During their observation, they found the algae to have a B12-independent methionine synthase fusion protein (MetE). The MetE gene isn't new, but was previously believed not to have been possessed by P. antarctica. MetE gives the algae the flexibility to adapt to low vitamin B12 availability. "This study suggests that the reality is more complex. For most algae, maintaining a flexible metabolism for B12 is beneficial, given how scarce the vitamin's supply is in seawater," said Deepa Rao, lead researcher of the study and former MIT postdoc." Having this flexibility enables them to make essential amino acids, even when they can't obtain enough of the vitamin from the environment. Implying that the classification of algae as B12-requiring or not might be too simplistic" Antarctica, which lives at the base of the food web, has been thought to be entirely controlled by iron nutrition. The discovery of the MetE gene also indicates vitamin B12 likely plays a factor. Because of its presence in P. antarctica, the adaptability of the algae gives it a potential advantage to bloom in the early austral spring when the bacteria that produce B12, are scarcer. This discovery also has implications for climate change. The Southern Ocean, where P. antarctica is found, plays a significant role in the Earth's carbon cycle. P. antarctica takes in the CO2 and releases oxygen through photosynthesis. "As our global climate warms, there's increasing amounts of iron entering the coastal Southern Ocean from melting glaciers," Saito said. "Predicting what the next limiting thing after iron is important, and B12 appears to be one of them. Climate modelers want to know how much algae is growing in the ocean in order to get predictions right and they've parameterized iron, but haven't included B12 in those models yet." "We are particularly interested in knowing more about the extent of strain level diversity. It will be interesting to see if B12 independent strains have a competitive advantage in a warmer Southern Ocean," said co-author of the study Andy Allen, a joint professor at the J. Craig Venter Institute and the Scripps Institution of Oceanography at the University of California, San Diego. "Since there is a cost to B12 independence in terms of metabolic efficiency, an important question is whether or not strains that require B12 might become reliant on B12 producing bacteria." The discovery that P. antarctica has the ability to adapt to minimal vitamin B12 availability turns out to be true for many other species of algae that were also assumed to be strict B12 users previously. The findings from this study will pave the way for future research related to the carbon cycle and how different types of algae survive in the Southern Ocean's cold and harsh environment.