Drug discovery and development are complex and intricate processes, especially when it comes to treating a multifaceted disease like amyotrophic lateral sclerosis (ALS). At Target ALS, we fund research through a consortium model, pairing academic scientists with industry partners whose expertise in these processes expedites research from the lab to the clinic.
This blog shares insights into advancements in drug discovery and development for ALS, highlighting the cutting-edge research funded by Target ALS and its significant impact on the current and future clinical trial landscape.
Understanding ALS and the Need for New Therapeutics
ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness and, eventually, paralysis. The majority of ALS cases, around 90%, are sporadic, meaning they occur without a known genetic mutation or family history. This has made developing treatments particularly challenging. Traditional approaches have often targeted biological pathways or proteins altered late in the disease, which may explain the limited success of recent therapeutics.
Current FDA-approved treatments offer limited impact because they address the consequences of the disease rather than its initial causes. However, a new wave of therapeutics targeting upstream events in the disease’s biological cascade, including its causes, is now entering clinical testing. These innovative approaches aim to transform ALS treatment by targeting the root of the disease rather than just its symptoms.
Pioneering Efforts by Denali Therapeutics
Denali Therapeutics, a member of a few Target ALS-funded consortia, is focused on developing potential therapeutics that target stress granules. These granules are bundles of dysfunctional RNA and protein that aggregate or clump together when a cell is under stress. By preventing the formation of stress granules, the proteins that would become trapped within them can perform their necessary functions in the cell. One such trapped protein, TDP-43, is found aggregated in 95% of ALS cases.
Denali’s investigational drug, DNL343, is a small molecule designed to reduce the overactive cellular stress response by binding to a specific protein. This approach targets an upstream biological pathway, potentially altering the disease’s course rather than just alleviating symptoms. Denali has completed enrollment of their Phase 2/3 clinical trial, a major milestone in the drug discovery process. The rapid progress of DNL343 from an idea to a potential treatment in clinical trials exemplifies the success of the Innovation Ecosystem model promoted by Target ALS.
Advancements Approaching Clinical Trials
Building on its success, Denali Therapeutics is developing another program targeting a different protein that contributes to stress granule formation. This second program utilizes antisense oligonucleotide (ASO) technology to reduce levels of the target protein, thereby decreasing stress granule formation and reversing other negative effects associated with ALS.
Early-stage testing in mice has shown promising results, with the ASO treatment demonstrating good activity and tolerability. As the team prepares to test the molecule in animal models of ALS, they have also identified candidate biomarkers to confirm the drug’s activity in human patients, a crucial step for clinical trial success.
Targeting TDP-43: A Common ALS Protein
Given the prevalence of TDP-43 aggregation in ALS cases, this protein remains a significant target for research. Beyond Denali, Target ALS is funding additional companies, such as Dewpoint and Neumora, that are developing treatments targeting TDP-43. This support is crucial as these companies prepare for clinical trials.
QurAlis and Trace Therapeutics: Making Strides in Treatment
QurAlis and Trace Therapeutics are two other companies making significant advancements in ALS treatment development. Both focus on cryptic exons, an underlying mechanism of ALS identified through Target ALS-funded research.
Cryptic exons are sequences of RNA that are only present when TDP-43 dysfunction occurs, as it does in most ALS cases. These aberrant RNA sequences lead to the formation of aberrant proteins that can affect neuron health. Thus, eradicating these aberrant RNA or proteins may restore healthy function in neurons.
QurAlis is developing an ASO treatment, QRL-201, to correct a cryptic exon and restore normal levels of Stathmin 2, a gene essential for neuron growth and repair. In ALS, motor neurons die, so genes that promote neuron health are likely implicated. The company is currently enrolling ALS patients in a Phase I study to evaluate the treatment’s safety and tolerability.
Trace Therapeutics is targeting a cryptic exon in the gene Unc13a, which plays a crucial role in neurotransmitter release. Neurotransmitters are signaling chemicals that allow neurons to communicate with each other, a process that is disrupted in ALS.
Their ASO treatment has shown effectiveness in reversing ALS symptoms in mouse models, marking a significant step toward human trials.
Familial ALS and the C9orf72 Gene
Familial ALS, which accounts for 10% of all ALS cases, most often stems from a repeat expansion in the gene C9orf72. A repeat expansion is a repeated sequence of DNA that significantly affects a gene’s length and function. When this mutated gene is transcribed by RNA to become protein, both resulting strands of RNA (the sense and antisense strands) are incorrect. Aberrant proteins are created from each of these aberrant RNA strands, both of which could be toxic and lead to motor neuron degeneration.
Early clinical trials targeting the C9orf72 mutation have faced challenges. Many of these earlier therapies targeted the sense RNA strand, and new hypotheses are considering whether the antisense RNA strand should also be targeted. Target ALS is actively funding a range of new therapeutic avenues, including gene editing with CRISPR, Zinc Finger Nuclease, disiRNA, and ASOs.
Dr. Claire Clelland of UCSF is exploring CRISPR to remove the disease-causing DNA in the C9orf72 gene, offering a potentially groundbreaking therapy for ALS by targeting the initial cause of the disease. Meanwhile, companies like Ionis and Atalanta are developing treatments targeting the antisense RNA strand using ASOs and disiRNA, small molecules that bind to RNA to prevent the formation of toxic proteins.
Dr. Kathryn Morelli of the University of Vermont is utilizing zinc finger nuclease technology to target both sense and antisense RNA strands of the C9orf72 gene. This dual-target approach aims to eliminate both RNA strands, bypassing the question of which is actually toxic. Her research is progressing towards additional animal studies to support an investigational new drug application with the FDA.
Addressing Ultra-Rare Forms of ALS
While the primary focus of ALS drug discovery has been on more common forms of the disease, genomic sequencing has revealed ultra-rare genetic forms of ALS. Target ALS collaborates with organizations like the n-Lorem Foundation to develop ASO therapeutics for these ultra-rare forms, aiming to treat individuals more quickly and apply these learnings to broader ALS research.
A Promising Future for ALS Treatment
The landscape of ALS treatment is rapidly evolving, thanks to the innovative research and funding efforts of organizations like Target ALS. Researchers are making significant strides toward developing effective therapies by expanding the drug discovery pipeline and targeting upstream events in the disease’s biological cascade. The collaborative efforts of various pharma and biotech companies with academia, supported by Target ALS, highlight a promising future for ALS patients, caregivers, and advocates.
As we continue to explore and support groundbreaking research, the hope for effective ALS treatments becomes more tangible. The dedication and progress of the scientific community, fueled by the support of organizations like Target ALS, bring us closer to transforming ALS from a terminal diagnosis to a manageable condition.