In Vivo Selection of S/MAR Sequences to Favour AAV Episomal Maintenance in Dividing Cells.

Adeno-associated viral (AAV) vector-mediated gene therapy has emerged as a promising alternative to liver transplantation for monogenic metabolic hepatic diseases. AAVs are non-integrative vectors that are maintained primarily as episomes in quiescent cells like adult hepatocytes. This quality, while advantageous from a safety perspective due to a decreased risk of insertional mutagenesis, becomes a disadvantage when treating dividing cells, as it inevitably leads to the loss of the therapeutic genome.

Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16.

In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD).

Plain Radiography: A Unique Component of Spinal Assessment and Predictive Health.

While some research supports utilizing plain radiography for measuring biomechanical alignment of the spine for prognosis and treatment, there are contrasting viewpoints regarding both the value and utilization of these procedures in conservative care. Evaluation of both conservative and non-conservative approaches to spinal care revealed vast differences in radiographic utilization and interpretation between orthopedic surgeons, primary care physicians, chiropractic physicians, and physical therapists, which may account for the different viewpoints and rationales in the literature. A research summary is provided to explore any unique biomechanical parameters identified with plain radiography of the spine (PROTS) and how these measurements may relate to patient health.

Proactive enteral nutrition for patients undergoing allogeneic stem cell transplantation- implementation and clinical outcomes.

Background/ Objectives: Nutrition support is frequently required post allogeneic haematopoietic progenitor cell transplantation (HPCT) however the tolerance of enteral nutrition (EN) can vary. This mixed methods study aimed to explore staff perceptions, barriers and enablers to the use of EN post HPCT and report the implementation and outcomes of a nutrition protocol.

Subject/ Methods: A survey on barriers and enablers to the use of EN was developed and distributed to medical and nursing staff.

Safety, Feasibility, and Acceptability of a Multisite Individualized Exercise Intervention for People with Multiple Myeloma.

Introduction: High rates of disease- and treatment-related symptoms, such as bone lesions, in people with multiple myeloma (MM) create uncertainty on the safety and feasibility of exercise. This study determined the safety, feasibility, and acceptability of an individualized exercise medicine program for people with MM at any disease stage.

Methods: A multisite, randomized waitlist-controlled trial was conducted of an individualized, high-intensity aerobic, resistance, and impact-loading exercise program.

Relapsed nodular lymphocyte-predominant Hodgkin lymphoma presenting as severe paraneoplastic hepatitis: a case report.

Background: Hematological malignancies are an infrequent but important cause of liver dysfunction. There are several mechanisms by which this can occur, including direct malignant infiltration of the hepatic parenchyma and/or vasculature, vanishing bile duct syndrome, and paraneoplastic hepatitis. Paraneoplastic hepatitis is an extremely rare mechanism by which a hematological malignancy can cause liver dysfunction, and we present the first case, to our knowledge, of paraneoplastic hepatitis caused by nodular lymphocyte-predominant Hodgkin lymphoma in the literature.

Rescue of infant progressive familial intrahepatic cholestasis type 3 mice by repeated dosing of AAV gene therapy.

Background & Aims: Gene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration.

Gene therapy for liver diseases - progress and challenges.

Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results.

Gene Therapy for Acquired and Genetic Cholestasis.

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases.

A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector.

Background: Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors.

mRNA and gene editing: Late breaking therapies in liver diseases.

The efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver-targeted RNA delivery systems.

An Individualized Exercise Intervention for People with Multiple Myeloma-Study Protocol of a Randomized Waitlist-Controlled Trial.

People with multiple myeloma (MM) are second only to people with lung cancer for the poorest reported health-related quality of life (HRQoL) of all cancer types. Whether exercise can improve HRQoL in MM, where bone pain and lesions are common, requires investigation. This trial aims to evaluate the efficacy of an exercise intervention compared with control on HRQoL in people with MM.

Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia.

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months.

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model.

Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pah mouse model of PKU.

CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice.

Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR- ()Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir.

Nutrition support during allogeneic stem cell transplantation: evidence versus practice.

Purpose: Enteral (EN) or parenteral nutrition (PN) is frequently required during allogeneic haematopoietic progenitor cell transplantation (HPCT), however there is limited consensus on the appropriate mode and timing of nutrition support commencement. This study aimed to investigate current nutrition support practices in Australian allogeneic transplant units and explore barriers and enablers to the use of EN and PN.

Methods: All Australian adult allogeneic HPCT units were eligible to participate.

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4 mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers.

Pilot study investigating the effect of enteral and parenteral nutrition on the gastrointestinal microbiome post-allogeneic transplantation.

Nutrition support is frequently required post-allogeneic haematopoietic progenitor cell transplantation (HPCT); however, the impact of mode of feeding on the gastrointestinal microbiome has not been explored. This study aimed to determine if there is a difference in the microbiome between patients receiving enteral nutrition (EN) and parenteral nutrition (PN) post-allogeneic HPCT. Twenty-three patients received either early EN or PN when required.