Gene Therapy for Anemia???

Hello, Summarians!

Biotechnology has always changed healthcare. The pace and diversity with which it is changing is truly astounding. Here are a few examples.

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Searchlight DNA Panel in Dogs

Next-generation sequencing (NGS) has revolutionized the treatment of cancer in both humans and dogs, shifting the focus from a one-size-fits-all approach to personalized, biomarker-guided therapies. This change is facilitated by a growing understanding of cancer's genomic basis and the development of molecularly-guided treatment options, often tumor type-agnostic, supported by companion diagnostic tests. 

In veterinary oncology, a similar shift is seen. The growing knowledge about specific mutations in dogs with cancer is enhancing diagnosis, prognostication, and treatment. For instance, single gene-based tests are already in use for detecting BRAF mutations in urothelial carcinomas and KIT mutations in mast cell tumors. Moreover, genomic mutations are proving useful for prognosis (like the TP53 mutation in osteosarcoma indicating shorter survival) and for guiding targeted treatments (e.g., KIT mutations being sensitive to toceranib phosphate). 

However, there's a need for more comprehensive evaluation of mutation profiles in canine cancers. The increasing use of genome-wide profiling techniques is revealing a broader mutation landscape. One study involving 134 cancer-bearing dogs, profiled by Searchlight DNA, found mutation-level prognostic associations and assessed the impact of treatment decisions based on specific mutations. It identified genomic and clinical factors significantly associated with progression-free survival (PFS), with mutations in 6 genes linked to shorter PFS. 

The Searchlight DNA panel used in this study covers 120 key cancer genes and evaluates copy number variations (CNVs) and insertions/deletions (ITDs), as well as single nucleotide variations (SNVs). This comprehensive approach has sequenced over 1300 tumors, uncovering about 12,000 mutations. 

The study also underscored the effectiveness of targeted treatment, both informed and uninformed by genomic data. Drugs like toceranib, olaparib, sirolimus, and trametinib, when prescribed based on genomic findings, showed improvement in PFS. Genomically informed treatment particularly showed significant benefits, with about 30% of dogs living a year or more without disease progression. 

However, the study had limitations, including its retrospective nature and small sample size. Selection biases and variability in treatment approaches among different clinicians were also concerns. 

In summary, this research highlights the increasing role of genomics in veterinary oncology, showing how targeted treatments, guided by comprehensive genomic profiling, can potentially improve outcomes in dogs with cancer. As the field evolves, this approach may lead to even more significant improvements in patient outcomes. 

Chon, E, Sakthikumar, S, Tang, M, et al. Novel genomic prognostic biomarkers for dogs with cancer. J Vet Intern Med. 2023; 37(6): 2410-2421. doi:10.1111/jvim.16893 

Bottom line — Genomics can help with targeted treatment plans.

Gene Therapy in Cats

Chronic kidney disease (CKD) is a prevalent metabolic disease in geriatric cats, often leading to anemia, which contributes to disease progression and mortality. Traditional treatments include erythropoiesis-stimulating agents (ESAs) like epoetin alfa, but their effectiveness is limited due to the development of antibodies against these human-derived products. Recombinant feline erythropoietin (EPO) shows promise but is not commercially available. SB-001, a novel adeno-associated viral (AAV) based gene therapy, has been developed to address this unmet need. It delivers a feline EPO gene to muscle cells, enabling them to produce EPO. 

Initial trials with SB-001 in cats with CKD-associated anemia have been promising. The therapy led to increased packed cell volume (PCV), indicating enhanced erythropoiesis. This improvement in PCV was accompanied by better quality of life (QOL) indicators such as appetite, energy, and strength. However, interpreting QOL changes was challenging due to subjective assessment scales and variable owner compliance. 

The study also explored different dosing strategies, finding that a higher initial dose of SB-001 was more effective. Cats responded well, with sustained increases in PCV over time. Unlike injectable ESAs, SB-001 offers a more consistent, physiologic dose of EPO, potentially reducing the risk of adverse events seen with high-dose ESAs in humans. 

One drawback of SB-001 is its irreversibility, as it becomes incorporated into muscle cells. However, no significant issues like polycythemia were observed in the study. Non-responders to the treatment were typically cats with more severe comorbidities or those on multiple medications. 

The inability to measure the expressed feline EPO levels due to assay limitations and the variable EPO expression in different cats were among the challenges faced. Despite these limitations, no cats developed pure red cell aplasia (PRCA) or other severe side effects. The therapy also seemed to reduce the severity of CKD-associated anemia, potentially extending the survival time of these cats. 

In conclusion, SB-001 appears to be a promising treatment for non-regenerative anemia in elderly cats with CKD. Further studies are required to confirm its efficacy and safety and to establish the optimal dosing and management protocols. 

Vaden, SL, Kendall, AR, Foster, JD, et al. Adeno-associated virus-vectored erythropoietin gene therapy for anemia in cats with chronic kidney disease. J Vet Intern Med. 2023; 37(6): 2200-2210. doi:10.1111/jvim.16900 

Bottom line — Early results support this as a beneficial therapy.

Hydrolyzed Diets and Chronic Diarrhea in Dogs

This study explores the impact of dietary changes on dogs with chronic enteropathy (CE) and protein-losing enteropathies (PLE). It was found that diets with hydrolyzed proteins and moderate fat content could induce remission in dogs with CE and support recovery in dogs with PLE. Specifically, the study compared three diets: one with hydrolyzed fish, rice starch, and fish oil (HF), another adding prebiotics, turmeric, and high vitamin B12 to the HF diet (HF+), and a control diet with a mix of intact chicken, fish, corn, rice, chicken fat, and fish oil. 

The results showed that 83% of non-PLE dogs achieved remission through dietary changes alone, indicating that restricting ingredients rather than avoiding specific immunogenic antigens might be more effective. This challenges the notion of food-responsive CE being primarily driven by allergic reactions to common dietary antigens. 

In dogs with PLE, diets with hydrolyzed proteins and moderate fat improved body weight, serum albumin concentration, and sustained remission. However, the effectiveness of such diets as monotherapy is still uncertain due to the poor prognosis of PLE and the tendency of these dogs to refuse therapeutic diets or require concurrent medications. 

The study also found that incorporating vitamins like cobalamin (B12) and folate into the diet increased their serum concentrations in dogs with CE, suggesting dietary incorporation as a therapeutic approach. This could potentially eliminate the need for external supplementation. However, the study noted substantial individual variation in the response to these dietary changes. 

Despite these positive findings, the study acknowledges limitations, including a lack of endoscopic or histopathologic data for many dogs with CE and the specific patient population studied. The research highlights the need for further investigation into the role of diet in managing gastrointestinal diseases in dogs. 

Simpson, KW, Miller, ML, Loftus, JP, Rishniw, M, Frederick, CE, Wakshlag, JJ. Randomized controlled trial of hydrolyzed fish diets in dogs with chronic enteropathy. J Vet Intern Med. 2023; 37(6): 2334-2343. doi:10.1111/jvim.16844 

Bottom line — Another tool to help with these challenging cases.

Just putting things in perspective …