About

Gerry Lipshutz is a professor in the Pharmacology Department at the University of California, Los Angeles, serving as a faculty member since 2004. His research focuses on the development of gene and cell-based therapies for the treatment of metabolic diseases of the liver that commonly result in the development of intellectual disabilities in children. His active research directions include the development of gene-based therapies, such as adeno-associated virus and mRNA therapies, to restore nitrogen metabolism and ureagenesis. Additionally, he explores the neurobiology underlying arginase deficiency to better understand the neuropathology associated with this enzyme deficiency.

Research topics

• Medicine
• Biology
• Internal medicine
• Surgery
• Immunology

Selected publications

• A hybrid piggyBac AAV-transposon and LNP-transposase for treating arginase deficiency: A 100-fold dose reduction compared to AAV alone

  Molecular Therapy · 2026-04-01

  articleSenior author
  PublisherDOI

• P104: Gene-specific ACMG/AMP variant classification rules for ornithine transcarbamylase, N-acetylglutamate synthase, and carbamylphosphate synthetase 1*

  Genetics in Medicine Open · 2026-01-01

  articleOpen access

  Methods: A systematic literature search was conducted to address the scope and frequency of ophthalmic, renal/genitourinary, neurological/neurodevelopmental manifestations in publications from January 1998 to March 2025.Every reported case was curated individually, and associated manifestations were compiled using structured Human Phenotype Ontology (HPO) terminology in an Airtable relational database.Demographics, age of onset, body mass index (BMI), and gene variants were also captured in the database.After deduplication and cleaning, data were analyzed at the child and parent term ontology levels.Corrected frequencies (percent affected over screened) were reported for the entire dataset, by age group, and by gene altered, together with median age of onset and interquartile range (IQR) for each manifestation.Results: Out of 415 screened publications, we identified 261 containing individual patient data eligible for curation.From these, 1,776 individual patients (44.8% male, 36.6% female, and 18.6% unspecified) were cataloged for over 500 manifestations.Ethnicity was sparsely reported.Among cataloged cases, 86.2% received genetic testing.Variants were reported for 93.2% of tested patients and among them, 24.0% had at least one variant in BBS1, 18.8% in BBS10, 12.5% in BBS2, and 8.3% in BBS12.The most frequent variant was BBS1 M390R (13.1%) followed by BBS10 C91LfsX5 (5.6%).Patients with likely biallelic results in the most frequently altered genes were grouped into BBS1 (N=347), BBS10 (279), BBS2 (123), and BBS12 (107) cohorts for phenotypic analysis.Among ophthalmological manifestations, rod-cone dystrophy was highest in BBS2 (92.9%) and lowest in BBS12 (69.8%).Night blindness, an early symptom of retinal disease, was more commonly reported in BBS1 (93.2%) and BBS10 (95.4%) than in BBS2 (86.4%), and lowest in BBS12 (57.7%).BBS1 cases had the highest median age of onset of rod-cone dystrophy (21.5 years), presenting in young adults.The median age of onset for all other groups was 13-14 years.Abnormalities of the kidney overall ranged from 36.3% (BBS1) to 53.4% (BBS10).Renal cysts were more commonly recorded with BBS12 cases (45.5%) than in the other groups (23.1-33.9%).Reports of chronic kidney disease, instead, were highest in BBS10 (17.7%) and BBS2 (13.3%) than in BBS1 (8.0%) and BBS12 (6.7%).Genitourinary abnormalities were more commonly documented in BBS2 (70.8%) and BBS12 (66.7%).Neurodevelopmental delay was highest in BBS10 (69.9%) with similar prevalence in all other groups (57.8-60.0%),yet intellectual disability was less commonly mentioned in BBS10 (35.7%).Overall, when compared with frequencies in the original Beales criteria, chronic kidney disease, renal cysts, and neurodevelopmental delay appear to be more frequent in published cases, while other manifestations (eg, ataxia, speech deficit, and micropenis) are less frequently reported. Conclusion:The analysis of 1,776 individual published patients linked with discrete HPO phenotypes and genetic data supports the existing understanding that not every major feature is present in all patients, presenting a diagnostic challenge.The data confirmed that there is heterogeneity in BBS clinical presentations, or prevalence and age of onset of certain manifestations, in patients with biallelic variants in one of four BBS-associated genes studied.As genetic testing is integrated into standard practice, knowledge of genotype-phenotype correlations becomes increasingly critical in the counseling and management of patients.Future analyses of this dataset could help define the minimal constellation of clinical manifestations that, in the presence of biallelic variants, establishes a molecular diagnosis of BBS, redefining the current diagnostic approach.

  PublisherOA PDFDOI

• Guanidino compounds with native GABA(A) δ receptor selectivity: a tale of homeostatic compensation in δ-KO mice

  BMC Neuroscience · 2025-12-11

  articleOpen accessSenior author

  Altered GABAergic transmission has been implicated in the neurological symptoms of metabolic disorders associated with guanidino compound (GC) accumulation. Building on previous findings that selected GCs act as direct orthosteric GABAA​ receptor (GABAR) agonists, we now asked whether these GCs act preferentially on high-affinity extrasynaptic δ subunit-containing receptors (δ-GABAs). Using whole-cell patch clamp recordings from mouse cerebellar granule cells (CGCs) in brain slices of wild-type and δ-subunit knockout (δ-KO) mice, together with 5 nM [³H]muscimol displacement assays on WT and δ-KO forebrains, we compared the actions of four structurally GABA-like GCs — guanidinoacetate (GAA), β-guanidinopropionate (β-GPA), guanidinoethanesulfonate (GES), and γ-guanidinobutyrate (γ-GBA). These compounds activated CGC GABARs in cumulative concentration-response curves and displaced the highly δ-GABAR-selective ligand [3H]muscimol suggesting δ-GABAR-selective orthosteric agonist actions. In δ-KO forebrains, total [³H]muscimol binding was reduced by ~ 50%, confirming the loss high-agonist-affinity but low-abundance (~ 5% of total forebrain GABARs) δ-GABARs. δ-KO CGCs showed markedly reduced agonist sensitivity, with EC₅₀ values (µM, WT/δ-KO): GABA (2/6) < β-GPA (3/8) < GAA (4/14) < GES (32/72) < γ-GBA (44/219). The modest loss of agonist sensitivity for GABA and the four GABA-mimetic GCs in δ-KO CGCs is consistent with compensatory upregulation of non-δ extrasynaptic GABARs containing only α and β subunits, as previously described (Tretter et al., JBC 2001), explaining the preserved tonic inhibition in δ-KO neurons. Our findings demonstrate that GABA-mimetic GCs preferentially target δ-GABARs and suggest that homeostatic compensation by αβ-type GABARs is a key adaptive mechanism maintaining inhibitory tone in δ-KO CGC neurons.

  PublisherDOI

• Abstract No. 92 ▪ FEATURED ABSTRACT Dr. Boardwell: Development of an AI Interventional Radiology Expert for Real-Time Conversational Oral Boards Simulation and Case-Based Resident Training

  Journal of Vascular and Interventional Radiology · 2025-02-19

  articleOpen access
  PublisherOA PDFDOI

• [18F]FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation

  Scientific Reports · 2025-03-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Abstract Pathogenic variants in the creatine transporter gene SLC6A8 , reported to represent 2% of all intellectual disabilities in males, result in a spectrum of behavioral abnormalities including developmental delay, intellectual disability, and deficit in speech. While at present there are no effective treatments available, preclinical development and testing of gene therapy and other approaches to increase brain creatine are being actively pursued. In studying a mouse model of the disorder, [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-based positron emission tomography (PET)/computed tomography (CT) was performed to assess brain glucose metabolism in wild type and creatine transporter mutant mice ( Slc6a8 -/y ). The findings demonstrate marked differences in glucose metabolism in the brains of wild type and Slc6a8 -/y mice. In conducting behavioral phenotyping studies, notable abnormalities in behavior in the murine model led to additional studies in serotonin-mediated activity. Serotonergic signaling differences were detected between wild type and Slc6a8 -/y mice using 4-(2′-methoxyphenyl)-1-[2′-( N -2″-pyridinyl)- p -[ 18 F]fluorobenzamido]ethylpiperazine ([ 18 F]MPPF). These data demonstrate that [ 18 F]FDG-PET and [ 18 F]-MPPF-PET may serve as appropriate and sensitive biomarkers that could be used to assess the efficacy of not only new approaches in treating mutations of the creatine transporter SLC6A8 and their effectiveness in normalizing brain metabolism but also in enhancing our understanding of the mechanism of brain dysfunction that occurs in this complex brain disorder.

  PublisherOA PDFDOI

• Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control

  Molecular Therapy — Nucleic Acids · 2025-02-03 · 3 citations

  articleOpen accessSenior author

  mice, while all null vector-injected controls died with marked hyperammonemia; female mice demonstrated improved survival over treated males. While glutamine remained elevated compared to controls, ammonia was controlled in surviving animals. Mice maintained their weights and were not sarcopenic. While drinking water did contain carglumic acid, no nitrogen scavengers were administered. Although there were concerns with vector genomic integrity, these findings demonstrate proof of concept for an oversized gene-therapy approach for a challenging urea-cycle disorder where high-level hepatic protein is essential for survival.

  PublisherDOI

• A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system

  Disease Models & Mechanisms · 2025-05-27 · 1 citations

  articleOpen accessSenior author

  Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with dysfunction of Cps1 that could be detected biochemically. Characterization, based on the orthologous human variant Asn674Ile, revealed that the variant is reproducible, 100% penetrant and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate, and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.

  PublisherOA PDFDOI

• Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency

  Orphanet Journal of Rare Diseases · 2025-08-07 · 1 citations

  articleOpen access

  BACKGROUND: Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients with either condition commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to conduct clinical trials on potential treatments for these disorders are made more difficult by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consistent use of outcomes in studies. The current effort included patient and caregiver perspectives into the outcome selection of a COS for CTD and GAMT. RESULTS: We partnered with caregivers and health professionals to establish the first COS for CTD and GAMT. The COS developed includes seven outcomes ("Adaptive Functioning", "Cognitive Functioning", "Emotional Dysregulation", "MRS Brain Creatine", "Seizure/Convulsions", "Expressive Communication", and "Fine Motor Functions") for both CTD and GAMT, and an additional outcome for GAMT ("Serum/Plasma Guanidinoacetate") that are important to stakeholders and consequently should be considered for measurement in every clinical trial. Caregivers were valued partners throughout the COS development process, which increased community engagement and facilitated caregiver empowerment. CONCLUSIONS: Development of this COS illustrates a patient-centered approach for clinical trial readiness for CTD and GAMT that if utilized will make clinical trial results comparable, minimize bias in clinical trial outcome selection, and promote efficient use of resources.

  PublisherOA PDFDOI

• Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport

  Human Genetics and Genomics Advances · 2025-08-07

  articleOpen accessSenior author

  Creatine phosphate is a high-energy molecule essential for the normal functioning of highly metabolically active organs and tissues. SLC6A8 encodes the only known creatine transporter in humans (CRT1); pathogenic variants result in a neurophenotype that includes intellectual disability, seizures, and autistic-like behaviors. Due to the importance of creatine phosphate in normal brain function, we compared the amino acid sequence among a group of terrestrial mammals and zebrafish. Finding high interspecies invariance, we (1) sought to quantitatively assess the effect of a number of existing disease-causing SLC6A8 variants on in vitro creatine uptake, comparing variant type/location, along with (2) the reported effect of missense variants on severity classification. Creatine uptake in the pathogenic variants studied demonstrated that the vast majority had a profound effect on uptake; only 1, in a peripheral extracellular loop, had a moderately reduced effect. Of the missense variant analysis, those occurring in C and N termini were tolerated more, while variants in transmembrane domains tended to more likely affect function. While the high degree of amino acid conservation across terrestrial mammals underscores its evolutionary importance, together with the variant analysis, these findings provide a framework for understanding genotype-phenotype correlations in variants of CRT1 and highlight the critical functional constraints.

  PublisherDOI

• Staying on target in gene and cell therapy

  Molecular Therapy · 2024-08-23 · 1 citations

  editorialOpen access
  PublisherOA PDFDOI

Recent grants

• Investigation of Neuroanatomical Alterations in Arginase Deficiency After Neonatal Gene Therapy

  NIH · $154k · 2017–2020

• NIH Grant R56AI108826

  NIH · $513k · 2017

• NIH Grant R21NS091654

  NIH · $193k · 2017

• NIH Grant K08HD057555

  NIH · $455k · 2012

• NIH Grant R21NS09165402

  NIH · $231k · 2018

Frequent coauthors

• Brian Truong

  Poseida Therapeutics (United States)

  24 shared

• Ronald W. Busuttil

  University of California, Los Angeles

  22 shared

• Stephen D. Cederbaum

  18 shared

• Gabriel M. Danovitch

  University of California, Los Angeles

  17 shared

• Agustin Vega-Crespo

  APLA Health

  17 shared

• Patrick Lee

  Resources For The Future

  16 shared

• James Byrne

  16 shared

• Alan Wilkinson

  15 shared